Process for producing pyrrole compound

ABSTRACT

The present invention provides a production method of a sulfonylpyrrole compound useful as a pharmaceutical product, a production method of an intermediate used for the method, and a novel intermediate. The present invention relates to a method of producing sulfonylpyrrole compound (VIII), which includes reducing compound (III) and hydrolyzing the reduced product to give compound (IV), subjecting compound (IV) to a sulfonylation reaction to give compound (VI), and subjecting compound (VI) to an amination reaction.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 16/691,912 filed Nov. 22, 2019, which is a divisional application ofU.S. application Ser. No. 16/200,178 filed Nov. 26, 2018, which is adivisional application of U.S. application Ser. No. 14/994,360 filedJan. 13, 2016, which is a divisional application of U.S. applicationSer. No. 14/303,238 filed Jun. 12, 2014, which is a divisionalapplication of U.S. application Ser. No. 13/203,441 filed Aug. 25, 2011,which is the U.S. national stage pursuant to 35 U.S.C. § 371, ofInternational Application Ser. No. PCT/JP2010/052874 filed on Feb. 24,2010 and published as WO2010/098351 A1 on Sep. 2, 2010, which claims thebenefit of priority of Japanese Application No. 2009-042974, filed Feb.25, 2009, which are hereby expressly incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a production method of a pyrrolecompound useful as a pharmaceutical product, particularly an acidsecretion inhibitor, a production method of an intermediate used forthis method, a novel intermediate and the like.

BACKGROUND OF THE INVENTION

A pyrrole compound having a substituted sulfonyl group at the 1-position(hereinafter to be referred to as a sulfonylpyrrole compound) is usefulas an acid secretion inhibitor (proton pump inhibitor), a therapeuticdrug for a neoplastic disease or an autoimmune disease (patent documents1-3).

For example, patent document 2 describes, as a compound having an acidsecretion suppressive activity, a compound represented by the formula:

wherein r¹ is a monocyclic nitrogen-containing heterocyclic groupoptionally condensed with a benzene ring or a heterocycle, wherein themonocyclic nitrogen-containing heterocyclic group optionally condensedwith a benzene ring or a heterocycle optionally has substituent(s), r²is an optionally substituted C₆₋₁₄ aryl group, an optionally substitutedthienyl group or an optionally substituted pyridyl group, r³ and r⁴ areeach a hydrogen atom, or one of r³ and r⁴ is a hydrogen atom and theother is an optionally substituted lower alkyl group, an acyl group, ahalogen atom, a cyano group or a nitro group, and r⁵ is an alkyl group,or a salt thereof.

Patent document 2 describes, as a production method of a sulfonylpyrrolecompound, the following method using a pyrrole-3-carboxylate:

Patent document 3 describes the following production method of asulfonylpyrrole compound:

wherein Q is chlorine, bromine or iodine.

On the other hand, the following method is known as a production methodof a 2-halogeno-3-cyanopyrrole compound.

Patent document 4

As a method for producing a 3-cyanopyrrole compound from a2-halogeno-3-cyanopyrrole compound, the following methods are known.

Non-patent document 1, Non-patent document 2

Non-patent document 3

As a method for producing a 3-formylpyrrole compound from a3-cyanopyrrole compound, the following methods are known.

Non-patent document 4

Patent document 5

In addition, as a 3-cyanopyrrole compound, the following compounds areknown.

Patent document 6

Patent document 7

TABLE 1 w_(a) x_(a) y_(a) z_(a) R^(d) 3-CN 4-Cl 5-Cl 2-(p-CF₃O—C₆H₅)C₂H₅ 4-NO₂ 2-Br 3-Br 5-(p-Cl—C₆H₅) C₂H₅ 4-NO₂ 2-Cl 3-Cl5-(3,4-diCl—C₆H₅) C₂H₅ 4-NO₂ 2-Cl 3-Cl 5-(p-Br—C₆H₅) C₂H₅ 3-CN 4-Cl 5-Cl2-(p-CF₃—C₆H₅) C₂H₅ 3-CN 4-Cl 5-Cl 2-(3,4-diCl—C₆H₅) C₂H₅ 3-CN 4-Cl 5-Cl2-(p-Cl—C₆H₅) C₂H₅ 4-NO₂ 2-(p-Cl—C₆H₅) 5-CF₃ 2-(p-Cl—C₆H₅) C₂H₅ 3-CN4-Br 5-Br 2-Br C₂H₅ 3-CN 4-Br 5-CF₃ 2-(p-Cl—C₆H₅) C₂H₅ 3-CN 4-Cl 5-CF₃2-(p-Cl—C₆H₅) C₂H₅ 4-NO₂ 3-(p-Cl—C₆H₅) 5-CF₃ 2-(p-Cl—C₆H₅) C₂H₅ 3-NO₂4-(3,4-diCl—C₆H₅) 5-CF₃ 2-(p-Cl—C₆H₅) C₂H₅ 4-NO₂ 3-(m-CN—C₆H₅) 2-CF₃5-(p-Cl—C₆H₅) C₂H₅ 3-CN 4-Br 5-Br 2-(p-CF₃—C₆H₅) C₂H₅ 3-CN 2-Cl 4-Cl5-(3,4-diCl—C₆H₅) C₂H₅ 3-CN 2-Cl 4-Br 5-(p-Br—C₆H₅) C₂H₅Patent document 8

Patent document 9

Patent document 10

TABLE 2 Compound No Qn x_(b) y_(b) z_(b) 2-5 3-Cl H CN H 2-6 3-Cl CH₃ CNH 2-7 3-Cl Cl CN H 2-8 3-Cl Br CN H 2-31 3-Cl H CN CH₃ 2-32 3-Cl H CNCHO 2-57 3-Me H CN H 2-58 3-Me CH₃ CN H 2-59 3-Me Cl CN H 2-60 3-Me BrCN H 2-72 3-Me H CN CH₃ 2-73 3-Me H CN CHO 2-92 3-cyclopropyl H CN H2-93 3-cyclopropyl CH₃ CN H 2-94 3-cyclopropyl Cl CN H 2-953-cyclopropyl Br CN H 2-108 3-cyclopropyl H CN CH₃ 2-109 3-cyclopropyl HCN CHO

TABLE 3 Compound No Qn x_(b) y_(b) z_(b) 2-128 5-cyclopropyl H CN H2-129 5-cyclopropyl CH₃ CN H 2-130 5-cyclopropyl Cl CN H 2-1315-cyclopropyl Br CN H 2-145 5-cyclopropyl H CN CH₃ 2-146 5-cyclopropyl HCN CHO 2-157 5-Et H CN H 2-158 5-Et CH₃ CN H 2-159 5-Et Cl CN H 2-1605-Et Br CN H 2-175 5-Et H CN CH, 2-176 5-Et H CN CHO 2-195 3-C≡CH H CN H2-196 3-C≡CH CH₃ CN H 2-197 3-C≡CH Cl CN H 2-198 3-C≡CH Br CN H 2-2123-C≡CH H CN CH₃ 2-213 3-C≡CH H CN CHO

In addition, as a 2-mercaptopyrrole derivative, the following compoundsare known.

For example, non-patent document 5 describes 2-mercaptopyrrolederivative (A) having a cyano group at the 3-position:

non-patent document 6 describes 2-mercaptopyrrole derivative (B) havinga cyano group at the 3-position:

patent document 11 describes 2-mercaptopyrrole derivative (C) having acyano group at the 3-position:

patent document 12 describes 2-mercaptopyrrole derivative (D) having acyano group at the 3-position:

As a synthesis method of these 2-mercaptopyrrole derivatives having acyano group at the 3-position, non-patent document 5 describes, as shownin the following reaction scheme, a synthesis method of mercaptopyrrolederivative (A) by a reaction of a (2-oxoethyl)malononitrile derivativewith hydrogen sulfide; however, a desulfurization reaction is notdescribed.

In addition, non-patent document 6 describes, as shown in the followingreaction scheme, a synthesis method of 2-mercaptopyrrole derivative (B)having a cyano group at the 3-position is described; however, it is notby a ring closure reaction of a (2-oxoethyl)malononitrile derivative anda sulfur compound. Furthermore, a desulfurization reaction of theobtained 2-mercaptopyrrole derivative is not described.

Moreover, patent document 11 describes, as shown in the followingreaction scheme, a synthesis method of 2-mercaptopyrrole derivative (C)having a cyano group at the 3-position; however, it is not by a ringclosure reaction of a (2-oxoethyl)malononitrile derivative and a sulfurcompound. Furthermore, a desulfurization reaction of the obtained2-mercaptopyrrole derivative is not described.

Moreover, patent document 12 describes, as shown in the followingreaction scheme, a synthesis method of 2-mercaptopyrrole derivative (D)having a cyano group at the 3-position; however, it is not by a ringclosure reaction of a (2-oxoethyl)malononitrile derivative and a sulfurcompound. In addition, a desulfurization reaction of the obtained2-mercaptopyrrole derivative is not described.

DOCUMENT LIST Patent Documents

-   patent document 1: WO2006/036024-   patent document 2: WO2007/026916-   patent document 3: WO2004/103968-   patent document 4: JP-A-6-9554-   patent document 5: U.S. Pat. No. 4,904,687-   patent document 6: EP-A-358047-   patent document 7: EP-A-491136-   patent document 8: U.S. Pat. No. 5,359,090-   patent document 9: U.S. Pat. No. 5,563,279-   patent document 10: JP-A-10-324687-   patent document 11: WO2005/040110-   patent document 12: WO2006/064944

Non-Patent Documents

-   non-patent document 1: J. Med. Chem., 1995, 38 (12), 2158-2165-   non-patent document 2: Nucleosides Nucleotides, 1997, 16 (7-9),    941-944-   non-patent document 3: J. Med. Chem., 1995, 38 (20), 4106-4144-   non-patent document 4: Can. J. Chem., 1980, 58, 409-411-   non-patent document 5: Chemistry Heterocyclic Compound, 1992, vol.    2, page 277-   non-patent document 6: Tetrahedron, 1991, vol. 47, page 8243

SUMMARY OF THE INVENTION

A more efficient production method of a sulfonylpyrrole compound usefulas a pharmaceutical product is desired. In addition, provision of anintermediate used for this method is desired.

The present inventors have intensively studied a production method of asulfonylpyrrole compound useful as an acid secretion inhibitor,particularly a compound represented by the formula (VIII):

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R³ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andR⁴ is an alkyl group, or a salt thereof. As a result, they have found anovel production method of a sulfonylpyrrole compound, which uses a3-cyanopyrrole compound. In addition, they have found a novel productionmethod of a 3-cyanopyrrole compound, which is an intermediate, and anovel intermediate, which resulted in the completion of the presentinvention.

Accordingly, the present invention relates to the following invention.

(1) A method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R³ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andR⁴ is an alkyl group, or a salt thereof, comprising(I) reducing a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, andhydrolyzing the reduced product to give a compound represented by theformula

wherein each symbol is as defined above, or a salt thereof,(II) reacting the obtained compound with a compound represented by theformulaR³—SO₂—X  (V)wherein R³ is as defined above and X is a leaving group, or a saltthereof, to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, and(III) reacting the obtained compound with a compound represented by theformulaR⁴—NH₂  (VII)wherein R⁴ is as defined above, or a salt thereof, in the presence of areducing agent;(2) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, or a salt thereof, comprisingsubjecting a compound represented by the formula

wherein X₁ is a halogen atom and other symbols are as defined above, ora salt thereof, to dehalogenation;(3) the production method of the aforementioned (2), wherein thedehalogenation is performed in the presence of a base;(4) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, or a salt thereof, comprising reducinga compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, andhydrolyzing the reduced product;(5) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R⁵ is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup or a group represented by —S—R⁶ (R⁶ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group), andn is 0, 1 or 2, or a salt thereof, comprising reacting a compoundrepresented by the formula

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the formulaR⁵S(O)_(n)Hwherein R⁵ and n are as defined above, or a salt thereof; (6) a methodof producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, or a salt thereof, comprisingsubjecting a compound represented by the formula

wherein R¹ and R² are as defined above, R⁵ is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup or a group represented by —S—R⁶ (R⁶ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group), andn is 0, 1 or 2, or a salt thereof, to a desulfurization reaction;(7) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R³ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andR⁴ is an alkyl group, or a salt thereof, comprising(I) reacting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the formulaR⁵S(O)_(n)Hwherein R⁵ is an optionally substituted hydrocarbon group, an optionallysubstituted heterocyclic group, an acyl group or a group represented by—S—R⁶ (R⁶ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group), and n is 0, 1 or 2, or asalt thereof, to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, (II)subjecting the obtained compound to a desulfurization reaction to give acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof, (III)reacting the obtained compound with a compound represented by theformulaR³—SO₂—X  (V)wherein R³ is as defined above, and X is a leaving group, or a saltthereof, to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof,(IV) reducing the obtained compound and hydrolyzing the reduced productto give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, and(V) reacting the obtained compound with a compound represented by theformulaR⁴—NH₂  (VII)wherein R⁴ is as defined above, or a salt thereof; (8) a method ofproducing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, or a salt thereof, comprisingsubjecting a compound represented by the formula

wherein m is 0 or 1 and other symbols are as defined above, or a saltthereof, to a desulfurization reaction;(9) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, or a salt thereof, comprising reactinga compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, with asulfur reagent to give a compound represented by the formula

wherein m is 0 or 1, and other symbols are as defined above, or a saltthereof, and subjecting the obtained compound to a desulfurizationreaction;(10) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R⁷ is a cyano group or asubstituted carboxyl group, and R⁸ is a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, a chlorine atom or a fluorine atom, or a salt thereof, comprisingsubjecting a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, to areduction reaction;(11) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R⁷ is a cyano group or asubstituted carboxyl group, and R⁸ is a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, a chlorine atom or a fluorine atom, or a salt thereof, comprisingcyclizing a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof;(12) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R⁷ is a cyano group or asubstituted carboxyl group, and R⁸ is a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, a chlorine atom or a fluorine atom, or a salt thereof, comprisingreducing a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, andcyclizing the reduced product;(13) a method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and R⁸ is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, a chlorine atom or a fluorine atom, or a saltthereof, comprising cyclizing a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, in thepresence of a reducing agent;(14) a compound represented by the formula

wherein R^(1a) is an aryl group having substituent(s), or a saltthereof;(15) a compound represented by the formula

wherein R^(1b) is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R⁵ is an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an acyl group or a group represented by —S—R⁶ (R⁶ is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group), and n is 0, 1 or 2 (excluding2,2′-dithiobis(5-methyl-1H-pyrrole-3-carbonitrile),2,2′-dithiobis(5-phenyl-1H-pyrrole-3-carbonitrile),2,2′-dithiobis[5-(4-chlorophenyl)-1H-pyrrole-3-carbonitrile],2,2′-dithiobis[5-(4-methylphenyl)-1H-pyrrole-3-carbonitrile] and2,2′-dithiobis[5-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile]), or asalt thereof.

Effect of the Invention

According to the method of the present invention, since asulfonylpyrrole compound is obtained in a short step as compared toconventional methods, the sulfonylpyrrole compound can be produced at alow cost.

In addition, as a synthesis method of the above-mentioned intermediate3-cyanopyrrole compound, a (2-oxoethyl)malononitrile compound is reactedwith a sulfur compound to give a 2-mercapto-3-cyanopyrrole compound,which is then subjected to a desulfurization reaction to give the objectcompound in a high yield. Furthermore, 2-mercapto-3-cyanopyrrole can beused as a novel intermediate for a 3-cyanopyrrole compound.

The present invention relates to a production method of asulfonylpyrrole compound useful as an acid secretion inhibitor,particularly, a compound represented by the formula (VIII):

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R³ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andR⁴ is an alkyl group (hereinafter sometimes to be abbreviated ascompound (VIII)) or a salt thereof, a production method of anintermediate therefor and the like. Compound (VIII) or a salt thereofshows a highly strong proton pump inhibitory effect. Since compound(VIII) or a salt thereof inhibits the proton pump (H⁺/K⁺-ATPase)activity reversibly and in a K⁺ antagonist inhibitory manner toconsequently suppress acid secretion, it is sometimes referred to as apotassium-competitive acid blocker: P-CAB or an acid pump antagonist(APA). Compound (VIII) or a salt thereof rapidly expresses action, andshows maximum efficacy from the initial administration. Furthermore, itis characterized by a small influence of metabolism polymorphisms(dispersion among patients), low cytotoxicity, weak cytochrome P450(CYP) inhibitory activity and hERG inhibitory activity, and longduration of action. Therefore, compound (VIII) or a salt thereofobtained according to the production method of the present invention isuseful as an agent clinically useful for the prophylaxis and/ortreatment of peptic ulcer (e.g., gastric ulcer, duodenal ulcer,anastomotic ulcer, ulcer caused by non-steroidal anti-inflammatoryagents, ulcer due to postoperative stress etc.); Zollinger-Ellisonsyndrome; gastritis; erosive esophagitis; symptomatic gastroesophagealreflux disease (symptomatic GERD); Barrett esophagus, functionaldyspepsia; gastric cancer; stomach MALT lymphoma; gastric hyperacidity;or an inhibitor of upper gastrointestinal hemorrhage due to pepticulcer, acute stress ulcer, hemorrhagic gastritis or invasive stress orrecurrence of ulcer due to non-steroidal anti-inflammatory agents andthe like. Since compound (VIII) or a salt thereof shows low toxicity andis superior in water-solubility, in vivo kinetics and efficacyexpression, it is useful as a pharmaceutical composition. Moreover,since compound (VIII) or a salt thereof is stable even under acidicconditions, it can be administered orally as a conventional tablet andthe like without being formulated as an enteric-coated preparation. Thishas a consequence that the preparation of tablet and the like can bemade smaller, which is advantageous in that it is easily swallowed bypatients having difficulty in swallowing, particularly the elderly andchildren. In addition, since a sustained release effect afforded byenteric-coated preparations is absent, expression of a gastric acidsecretion-suppressive action is rapid, and alleviation of symptoms suchas pain and the like is rapid.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each symbol in the formula is explained in detail inthe following.

Examples of the halogen atom for X₁ include chlorine, bromine and thelike.

Examples of the “hydrocarbon group” of the “optionally substitutedhydrocarbon group” for R¹ include a chain or cyclic hydrocarbon group(e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl etc.). Ofthese, a chain or cyclic hydrocarbon group having a carbon number of 1to 16 and the like are preferable.

Examples of the “alkyl” include C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)and the like.

Examples of the “alkenyl” include C₂₋₆ alkenyl (e.g., vinyl, allyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl,1-methyl-2-propenyl, 2-methyl-1-propenyl etc.) and the like.

Examples of the “alkynyl” include C₂₋₆ alkynyl (e.g., ethynyl,propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl etc.) and thelike.

Examples of the “cycloalkyl” include C₃₋₇ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.) and the like.

Examples of the “aryl” include C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl,2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.)and the like.

Examples of the “aralkyl” include C₇₋₁₆ aralkyl (e.g., phenyl-C₁₋₆ alkylsuch as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl and the like, naphthyl-C₁₋₆ alkyl, diphenyl-C₁₋₄ alkyletc.) and the like.

When the above-mentioned hydrocarbon group is alkyl, alkenyl or alkynyl,it is optionally substituted by 1 to 3 substituents selected from (1) ahalogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, aniodine atom etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, a bromineatom, an iodine atom), (6) C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxyetc.), (7) C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy,diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy,2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy,5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆ alkylthio (e.g.,methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio etc.) optionally having 1 to 3 halogen atoms(e.g., fluorine atom, chlorine atom, bromine atom, iodine atom), (10)C₆₋₁₄ arylthio (e.g., phenylthio, naphthylthio etc.), (11) C₇₋₁₆aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio,1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.), (12)amino, (13) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.),(14) mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.), (15) mono-C₇₋₁₆ aralkylamino (e.g., benzylaminoetc.), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.),(17) di-C₆₋₁₄ arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆-14aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino (e.g., pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.)optionally containing, besides one nitrogen atom and carbon atom, 1 or 2kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.)containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, (48)C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), and the like.

In addition, when the above-mentioned hydrocarbon group is cycloalkyl,aryl or aralkyl, it is optionally substituted by 1 to 5 (preferably 1 to3) substituents selected from (1) a halogen atom (e.g., a fluorine atom,a chlorine atom, a bromine atom, an iodine atom etc.), (2) nitro, (3)cyano, (4) hydroxy, (5) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,fluoromethoxy etc.) optionally having 1 to 3 halogen atoms (e.g., afluorine atom, a chlorine atom, a bromine atom, an iodine atom), (6)C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy(e.g., benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom,iodine atom), (10) C₆₋₁₄ arylthio (e.g., phenylthio, naphthylthio etc.),(11) C₇₋₁₆ aralkylthio (e.g., benzylthio, phenethylthio,diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio,2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio,5-phenylpentylthio etc.), (12) amino, (13) mono-C₁₋₆ alkylamino (e.g.,methylamino, ethylamino etc.), (14) mono-C₆₋₁₄ arylamino (e.g.,phenylamino, 1-naphthylamino, 2-naphthylamino etc.), (15) mono-C₇₋₁₆aralkylamino (e.g., benzylamino etc.), (16) di-C₁₋₆ alkylamino (e.g.,dimethylamino, diethylamino etc.), (17) di-C₆₋₁₄ arylamino (e.g.,diphenylamino etc.), (18) di-C₇₋₁₆ aralkylamino (e.g., dibenzylaminoetc.), (19) formyl, (20) C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyletc.), (21) C₆₋₁₄ aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyletc.), (22) carboxyl, (23) C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), (24) C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), (25) carbamoyl, (26)thiocarbamoyl, (27) mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl etc.), (28) di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29)C₆₋₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl etc.), (30) C₁₋₆ alkylsulfonyl (e.g.,methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl etc.) optionallyhaving 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom, abromine atom, an iodine atom), (31) C₆₋₁₄ arylsulfonyl (e.g.,phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), (32) C₁₋₆alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), (33) C₆₋₁₄arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl,2-naphthylsulfinyl etc.), (34) formylamino, (35) C₁₋₆alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino (e.g., pyrrolidin-1-yl, piperidino,piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepin-1-yl etc.)optionally containing, besides one nitrogen atom and carbon atom, 1 or 2kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom, (47) a 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.)containing, besides carbon atom, 1 or 2 kinds of 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom, (48)C₁₋₃ alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), (50) C₁₋₆ alkyl group (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl etc.) optionallyhaving 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine),(51) a C₂₋₆ alkenyl group (e.g., allyl, isopropenyl, isobutenyl,1-methylallyl, 2-pentenyl, 2-hexenyl etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (52) a C₂₋₆alkynyl group (e.g., propargyl, 2-butynyl, 3-butynyl, 3-pentynyl,3-hexynyl etc.), (53) mono-C₃₋₇ cycloalkyl-carbamoyl (e.g.,cyclopropylcarbamoyl, cyclobutylcarbamoyl etc.), and (54) 5- to10-membered heterocyclyl-carbonyl containing, besides carbon atom, 1 or2 kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom (e.g., 4-morpholinocarbonyl etc.) and the like.

Examples of the “heterocyclic group” of the “optionally substitutedheterocyclic group” for R¹ include a 3- to 8-membered heterocyclic group(preferably a 5- or 6-membered heterocyclic group) containing 1 to 4hetero atoms such as a nitrogen atom (optionally oxidized), an oxygenatom, a sulfur atom (optionally mono- or dioxidized) and the like, or a3- to 8-membered heterocyclic group (preferably a 5- or 6-memberedheterocyclic group) containing 1 to 4 hetero atoms such as a nitrogenatom (optionally oxidized), an oxygen atom, a sulfur atom (optionallymono- or dioxidized) and the like, with a benzene ring; or a groupformed by condensing a 3- to 8-membered heterocyclic group (preferably5- or 6-membered heterocyclic group) containing 1 to 4 hetero atoms suchas a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom(optionally mono- or dioxidized) and the like, preferably a group formedby condensing the 5- or 6-membered heterocyclic group with a 5- or6-membered ring containing 1 to 4 hetero atoms such as a nitrogen atom(optionally oxidized), an oxygen atom, a sulfur atom (optionally mono-or dioxidized) and the like.

Specifically, aziridinyl (e.g., 1- or 2-aziridinyl), azirinyl (e.g., 1-or 2-azirinyl), azetyl (e.g., 2-, 3- or 4-azetyl), azetidinyl (e.g., 1-,2- or 3-azetidinyl), perhydroazepinyl (e.g., 1-, 2-, 3- or4-perhydroazepinyl), perhydroazocinyl (e.g., 1-, 2-, 3-, 4- or5-perhydroazocinyl), pyrrolyl (e.g., 1-, 2- or 3-pyrrolyl), pyrazolyl(e.g., 1-, 3-, 4- or 5-pyrazolyl), imidazolyl (e.g., 1-, 2-, 4- or5-imidazolyl), triazolyl (e.g., 1,2,3-triazole-1-, 4- or 5-yl,1,2,4-triazol-1-, 3-, 4- or 5-yl), tetrazolyl (e.g., tetrazol-1-, 2- or5-yl), furyl (e.g., 2- or 3-furyl), thienyl (e.g., 2- or 3-thienyl),thienyl wherein sulfur atom is oxidized (e.g., 2- or3-thienyl-1,1-dioxide), oxazolyl (e.g., 2-, 4- or 5-oxazolyl),isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3- or 5-yl,1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-, 4- or5-thiazolyl), isothiazolyl (e.g., 3-, 4- or 5-isothiazolyl),thiadiazolyl (e.g., 1,2,3-thiadiazol-4- or 5-yl, 1,2,4-thiadiazol-3- or5-yl, 1,2,5-thiadiazol-3-yl, 1,3,4-thiadiazol-2-yl), pyrrolidinyl (e.g.,1-, 2- or 3-pyrrolidinyl), pyridyl (e.g., 2-, 3- or 4-pyridyl), pyridylwherein nitrogen atom is oxidized (e.g., 2-, 3- or 4-pyridyl-N-oxide),pyridazinyl (e.g., 3- or 4-pyridazinyl), pyridazinyl wherein one or bothof nitrogen atoms is/are oxidized (e.g., 3-, 4-, 5- or6-pyridazinyl-N-oxide), pyrimidinyl (e.g., 2-, 4- or 5-pyrimidinyl),pyrimidinyl wherein one or both of nitrogen atoms is/are oxidized (e.g.,2-, 4-, 5- or 6-pyrimidinyl-N-oxide), pyrazinyl, piperidinyl (e.g., 1-,2-, 3- or 4-piperidinyl), piperazinyl (e.g., 1- or 2-piperazinyl),indolyl (e.g., 3H-indol-2-, 3-, 4-, 5-, 6- or 7-yl), pyranyl (e.g., 2-,3- or 4-pyranyl), thiopyranyl (e.g., 2-, 3- or 4-thiopyranyl),thiopyranyl wherein sulfur atom is oxidized (e.g., 2-, 3- or4-thiopyranyl-1,1-dioxide), morpholinyl (e.g., 2-, 3- or 4-morpholinyl),thiomorpholinyl, quinolyl (e.g., 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl),isoquinolyl, pyrido[2,3-d]pyrimidinyl (e.g.,pyrido[2,3-d]pyrimidin-2-yl), naphthyridinyl such as 1,5-, 1,6-, 1,7-,1,8-, 2,6- or 2,7-naphthyridinyl and the like (e.g., 1,5-naphthyridin-2-or 3-yl), thieno[2,3-d]pyridyl (e.g., thieno[2,3-d]pyridin-3-yl),pyrazinoquinolyl (e.g., pyrazino[2,3-d]quinolin-2-yl), chromenyl (e.g.,2H-chromen-2- or 3-yl), 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, 2,3-dihydro-1-benzofuranyl,2,1,3-benzothiadiazolyl, 2,3-dihydro-1,4-benzodioxin-5- or -6-yl,1,3-benzothiazol-6-yl, 1,1-dioxide-2,3-dihydro-1-benzothien-6-yl,1-benzothienyl and the like are used.

Examples of the “substituent” of the heterocyclic group include thosesimilar to the substituents optionally present when the “hydrocarbongroup” for the above-mentioned R¹ is cycloalkyl, aryl or aralkyl. Thenumber of the substituents is 1 to 5, preferably 1 to 3.

Examples of the “alkyl group” of the “optionally substituted alkylgroup” for R² include C₁₋₆ alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and thelike, and the like.

As the substituent that the “alkyl group” optionally has, (1) a halogenatom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atometc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy, fluoromethoxy etc.) optionally having 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (6) C₆₋₁₄aryloxy (e.g., phenyloxy, naphthyloxy etc.), (7) C₇₋₁₆ aralkyloxy (e.g.,benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy,2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy,4-phenylbutyloxy, 5-phenylpentyloxy etc.), (8) mercapto, (9) C₁₋₆alkylthio (e.g., methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio etc.) optionally having1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), (10)C6-1₄ arylthio (e.g., phenylthio, naphthylthio etc.), (11) C₇₋₁₆aralkylthio (e.g., benzylthio, phenethylthio, diphenylmethylthio,1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio,3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpentylthio etc.) (12)amino, (13) mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.),(14) mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.), (15) mono-C₇₋₁₆ aralkylamino (e.g., benzylaminoetc.), (16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.),(17) di-C₆₋₁₄ arylamino (e.g., diphenylamino etc.), (18) di-C₇₋₁₆aralkylamino (e.g., dibenzylamino etc.), (19) formyl, (20) C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl etc.), (21) C₆₋₁₄ aryl-carbonyl(e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), (22) carboxyl, (23) C₁₋₆alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl etc.), (24) C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl etc.), (25) carbamoyl, (26) thiocarbamoyl, (27)mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.),(28) di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl etc.), (29) C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), (30)C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), (31)C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), (32) C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl etc.), (33) C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), (34) formylamino, (35)C₁₋₆ alkyl-carbonylamino (e.g., acetylamino etc.), (36) C₆₋₁₄aryl-carbonylamino (e.g., benzoylamino, naphthoylamino etc.), (37) C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino etc.), (38) C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino etc.),(39) C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylaminb, 1-naphthylsulfonylamino etc.), (40) C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), (41) C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), (42) C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), (43) mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),(44) di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), (45) C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), (46) a 5- to 7-memberedsaturated cyclic amino optionally containing, besides one nitrogen atomand carbon atom, 1 or 2 kinds of 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom (e.g., pyrrolidin-1-yl,piperidino, piperazin-1-yl, morpholino, thiomorpholino,hexahydroazepin-1-yl etc.), (47) a 5- to 10-membered aromaticheterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.), (48) C₁₋₃alkylenedioxy (e.g., methylenedioxy, ethylenedioxy etc.), and (49) C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.) and the like can be mentioned.

The number of the substituents is 1 to 3.

As the “acyl group” for R², an acyl group having 1 to 20 carbon atoms,which is derived from organic carboxylic acid can be mentioned. Forexample, C₁₋₇ alkanoyl groups (e.g., formyl; C₁₋₆ alkyl-carbonyl such asacetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyland the like; etc.), C₆₋₁₄ aryl-carbonyl groups (e.g., benzoyl,naphthalenecarbonyl etc.), C₁₋₆ alkoxy-carbonyl groups (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl etc.), C₆₋₁₄ aryloxy-carbonyl groups (e.g.,phenoxycarbonyl group), C₇₋₁₉ aralkyl-carbonyl groups (e.g., phenyl-C₁₋₄alkylcarbonyl such as benzylcarbonyl, phenethylcarbonyl,phenylpropylcarbonyl and the like, benzhydrylcarbonyl, naphthyl-C₁₋₄alkylcarbonyl such as naphthylethylcarbonyl and the like, etc.), C₇₋₁₉aralkyloxy-carbonyl groups (e.g., phenyl-C₁₋₄ alkyloxycarbonyl such asbenzyloxycarbonyl and the like, etc.), 5- or 6-memberedheterocyclyl-carbonyl group or condensed heterocyclyl-carbonyl groupsthereof (e.g., a 5- or 6-membered heterocyclyl-carbonyl group containing1 to 4 hetero atoms such as nitrogen atom (optionally oxidized), oxygenatom, sulfur atom (optionally mono or dioxidized), e.g.,pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl and the like;pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and the like;imidazolylcarbonyl such as 2-, 4- or 5-imidazolylcarbonyl and the like;triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl,1,2,4-triazol-3-ylcarbonyl and the like; tetrazolylcarbonyl such as 1H-or 2H-tetrazol-5-ylcarbonyl and the like; furylcarbonyl such as 2- or3-furylcarbonyl and the like; thienylcarbonyl such as 2- or3-thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4- or5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as 3-, 4- or5-isoxazolylcarbonyl and the like; oxadiazolylcarbonyl such as1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl,1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and thelike; thiazolylcarbonyl such as 2-, 4- or 5-thiazolylcarbonyl and thelike; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl andthe like; thiadiazolylcarbonyl such as 1,2,3-thiadiazol-4- or5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-thiadiazol-3-or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl and the like;pyrrolidinylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl and the like;pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the like;pyridylcarbonyl wherein nitrogen atom is oxidized such as 2-, 3- or4-pyridyl-N-oxidocarbonyl and the like; pyridazinylcarbonyl such as 3-or 4-pyridazinylcarbonyl and the like; pyridazinylcarbonyl wherein oneor both nitrogen atoms are oxidized, such as 3-, 4-, 5- or6-pyridazinyl-N-oxidocarbonyl and the like; pyrimidinylcarbonyl such as2-, 4- or 5-pyrimidinylcarbonyl and the like; pyrimidinylcarbonylwherein one or both nitrogen atoms are oxidized, such as 2-, 4-, 5- or6-pyrimidinyl-N-oxidocarbonyl and the like; pyrazinylcarbonyl;piperidinylcarbonyl such as 2-, 3- or 4-piperidinylcarbonyl and thelike; piperazinylcarbonyl; indolylcarbonyl such as 3H-indol-2- or3-ylcarbonyl and the like; pyranylcarbonyl such as 2-, 3- or4-pyranylcarbonyl and the like; thiopyranylcarbonyl such as 2-, 3- or4-thiopyranylcarbonyl and the like; quinolylcarbonyl such as 3-, 4-, 5-,6-, 7- or 8-quinolylcarbonyl and the like; isoquinolylcarbonyl;pyrido[2,3-d]pyrimidinylcarbonyl (e.g.,pyrido[2,3-d]pyrimidin-2-ylcarbonyl); naphthyridinylcarbonyl such as1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinylcarbonyl and the like(e.g., 1,5-naphthyridin-2- or 3-ylcarbonyl);thieno[2,3-d]pyridylcarbonyl (e.g., thieno[2,3-d]pyridin-3-ylcarbonyl);pyrazinoquinolylcarbonyl (e.g., pyrazino[2,3-b]quinolin-2-ylcarbonyl);chromenylcarbonyl (e.g., 2H-chromen-2- or 3-ylcarbonyl etc.) and thelike), a 5- or 6-membered heterocyclyl-acetyl group (e.g., 5- or6-membered heterocyclyl-acetyl group containing 1 to 4 hetero atoms suchas nitrogen atom (optionally oxidized), oxygen atom, sulfur atom(optionally mono or dioxidized) and the like), such as 2-pyrrolylacetyl,3-imidazolylacetyl, 5-isoxazolylacetyl and the like, and the like can beused.

As regards the substituent of acyl group, for example, when theabove-mentioned acyl group is an alkanoyl group or alkoxy-carbonylgroup, the acyl group is optionally substituted by 1 to 3 alkylthiogroups (e.g., C₁₋₄ alkylthio such as methylthio, ethylthio,n-propylthio, isopropylthio and the like, and the like), halogen (e.g.,fluorine, chlorine, bromine, iodine), alkoxy groups (e.g., C₁₋₆ alkoxysuch as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and thelike, and the like), nitro groups, alkoxy-carbonyl groups (e.g., C₁₋₆alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like,and the like), alkylamino groups (e.g., mono- or di-C₁₋₆ alkylamino suchas methylamino, ethylamino, n-propylamino, n-butylamino,tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino,diethylamino, methylethylamino, di-(n-propyl)amino, di-(n-butyl)aminoand the like, and the like), alkoxyimino groups (e.g., C₁₋₆ alkoxyiminosuch as methoxyimino, ethoxyimino, n-propoxyimino, tert-butoxyimino,n-hexyloxy-imino and the like, and the like) or hydroxyimino.

When the above-mentioned acyl group is an aryl-carbonyl group, anaryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonylgroup, a 5- or 6-membered heterocyclyl-carbonyl group or a 5- or6-membered heterocyclyl-acetyl group, it is optionally substituted by 1to 5 (preferably 1 to 3) alkyl groups (e.g., C₁₋₆ alkyl such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and thelike, C₃₋₆ cycloalkyl such as cyclohexyl and the like, and the like),alkenyl groups (e.g., C₂₋₆ alkenyl such as allyl, isopropenyl,isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like, and thelike), alkynyl groups (e.g., C₂₋₆ alkynyl such as propargyl, 2-butynyl,3-butynyl, 3-pentynyl, 3-hexynyl and the like, and the like), alkoxygroups (e.g., C₁₋₆ alkoxy such as methoxy, ethoxy, n-propoxy,tert-butoxy, n-hexyloxy and the like, and the like), acyl groups [e.g.,C₁₋₇ alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, hexanoyl, heptanoyl and the like; C₆₋₁₄ aryl-carbonyl such asbenzoyl, naphthalenecarbonyl and the like; C₁₋₆ alkoxy-carbonyl such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl and the like; C₆₋₁₄ aryloxy-carbonyl such asphenoxycarbonyl and the like; C₇₋₁₉ aralkyl-carbonyl such as phenyl-C₁₋₄alkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl,phenylpropylcarbonyl and the like) and the like; C₇₋₁₉aralkyloxy-carbonyl such as phenyl-C₁₄ alkyloxy-carbonyl (e.g.,benzyloxycarbonyl and the like) and the like, and the like], nitro,amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g., fluorine,chlorine, bromine, iodine), or alkylthio groups (C₁₋₄ alkylthio such asmethylthio, ethylthio, n-propylthio, isobutylthio and the like, and thelike).

Examples of the “optionally substituted hydroxy group” for R² includehydroxy; C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, trifluoromethoxyetc.) optionally having 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine), C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy etc.),C₇₋₁₆ aralkyloxy (e.g., benzyloxy, phenethyloxy, diphenylmethyloxy,1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy,3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy etc.), C₁₋₆alkyl-carbonyloxy (e.g., acetoxy, propionyloxy etc.), C₆₋₁₄aryl-carbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy etc.), C₁₋₆alkoxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy,propoxycarbonyloxy, butoxycarbonyloxy etc.), mono-C₁₋₆alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.),di-C₁₋₆ alkyl-carbamoyloxy (e.g., dimethylcarbamoyloxy,diethylcarbamoyloxy etc.), C₆₋₁₄ aryl-carbamoyloxy (e.g.,phenylcarbamoyloxy, naphthylcarbamoyloxy etc.), and the like.

Examples of the “optionally substituted amino group” for R² includeamino; mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino etc.);mono-C₆₋₁₄ arylamino (e.g., phenylamino, 1-naphthylamino,2-naphthylamino etc.); mono-C₇₋₁₆ aralkylamino (e.g., benzylamino etc.);di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino etc.); di-C₆₋₁₄arylamino (e.g., diphenylamino etc.); di-C₇₋₁₆ aralkylamino (e.g.,dibenzylamino etc.); formylamino; C₁₋₆ alkyl-carbonylamino (e.g.,acetylamino etc.); C₆₋₁₄ aryl-carbonylamino (e.g., benzoylamino,naphthoylamino etc.); C₁₋₆ alkoxy-carbonylamino (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,tert-butoxycarbonylamino etc.); C7-16 aralkyloxycarbonylamino (e.g.,benzyloxycarbonylamino etc.); C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino etc.); C₆₋₁₄ arylsulfonylamino(e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino etc.) and the like.

Examples of the “optionally substituted hydrocarbon group” for R³include groups similar to the “optionally substituted hydrocarbon group”for the aforementioned R¹.

Examples of the “optionally substituted heterocyclic group” for R³include groups similar to the “optionally substituted heterocyclicgroup” for the aforementioned R¹.

Examples of the “leaving group” for X include halogen atoms such aschlorine, bromine and the like, a hydroxy group, a methanesulfonyloxygroup, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group,a p-toluenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, ano-nitrobenzenesulfonyloxy group and the like.

Examples of the “alkyl group” for R⁴ include C₁₋₄ alkyl groups such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyletc. and the like.

Examples of the “optionally substituted hydrocarbon group” for R⁵include groups similar to the “optionally substituted hydrocarbon group”for the aforementioned R¹.

Examples of the “optionally substituted heterocyclic group” for R⁵include groups similar to the “optionally substituted heterocyclicgroup” for the aforementioned R¹.

Examples of the “acyl group” for R⁵ include groups similar to the “acylgroup” for the aforementioned R².

Examples of the “optionally substituted hydrocarbon group” for R⁶include groups similar to the “optionally substituted hydrocarbon group”for the aforementioned R¹.

Examples of the “optionally substituted heterocyclic group” for R⁶include groups similar to the “optionally substituted heterocyclicgroup” for the aforementioned R¹.

Examples of the “substituted carboxyl group” for R⁷ include C₁₋₄alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl).

Examples of the “optionally substituted hydrocarbon group” for R⁸include groups similar to the “optionally substituted hydrocarbon group”for the aforementioned R¹.

Examples of the “optionally substituted heterocyclic group” for R⁸include groups similar to the “optionally substituted heterocyclicgroup” for the aforementioned R¹.

Examples of the “aryl group” of the “aryl group having substituent(s)”for R^(1a) include C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.) and the like.

Examples of the “substituent” of the aryl group include substituentssimilar to the substituents optionally present when the “hydrocarbongroup” for the above-mentioned R¹ is cycloalkyl, aryl or aralkyl. Thenumber of the substituents is 1 to 5, preferably 1 to 3.

Examples of the “optionally substituted hydrocarbon group” for R^(1b)include groups similar to the “optionally substituted hydrocarbon group”for the aforementioned R¹.

Examples of the “optionally substituted heterocyclic group” for R^(1b)include groups similar to the “optionally substituted heterocyclicgroup” for the aforementioned R¹.

As R³, a “nitrogen-containing monocyclic heterocyclic group optionallycondensed with a benzene ring or a heterocycle (as the heterocyclicgroup, groups similar to the heterocyclic group of the “optionallysubstituted heterocyclic group” for the aforementioned R¹ can bementioned)” (e.g., 5- or 6-membered aromatic nitrogen-containingmonocyclic heterocyclic groups such as thiazolyl, imidazolyl, pyrazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and the like)optionally substituted by 1 to 3 substituents selected from (i) halogen(e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano,(iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.), (vii) oxoand (viii) C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl etc.) is preferable.

As R³, particularly, a 6-membered nitrogen-containing aromaticheterocyclic group (e.g., pyridyl groups (e.g., 2-, 3- or 4-pyridyletc.), pyrimidinyl groups (e.g., 2-, 4- or 5-pyrimidinyl etc.),pyridazinyl groups (e.g., 3- or 4-pyridazinyl etc.) etc.) optionallysubstituted by 1 to 3 substituents selected from (i) halogen (e.g.,fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv)C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (vi) an amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) ispreferable, and a pyridyl group optionally substituted by 1 to 3substituents selected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy, hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1to 3) halogens (e.g., fluorine, chlorine, bromine, iodine) isparticularly preferable. As R³, a pyridyl group is particularlypreferable.

As R¹, [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano,(iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (v) acetyl, (vi)C₃₋₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl etc.), (vii) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl etc.), (viii) a C₁₋₆ alkyl group substituted by 1 to 3hydroxy (e.g., hydroxymethyl, hydroxyethyl etc.), (ix) C₁₋₆ alkylthio(e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (x) C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl etc.),

[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and(vii) amino is preferable.

Of these, as R¹, [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionallysubstituted by 1 to 5 (preferably 1 to 3) substituents selected from (i)a halogen atom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano,(iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl,

[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl, or[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and(vii) amino is preferable.

Particularly, [1] a phenyl group optionally substituted by 1 to 5(preferably 1 to 3) substituents selected from (i) a halogen atom (e.g.,fluorine, chlorine, bromine, iodine) and (ii) C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine),

[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), or

[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) lower (specifically C₁₋₆) alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine) is preferable.

Of those mentioned above, a preferable embodiment of R¹ include [1] aphenyl group optionally substituted by 1 to 5 substituents selected from(i) a halogen atom and (ii) C₁₋₆ alkyl optionally substituted by 1 to 5halogen atoms, [2] a pyridyl group optionally substituted by 1 to 4substituents selected from lower (C₁₋₆) alkyl, a halogen atom, alkoxy(C₁₋₆ alkoxy), cyano, acyl (e.g., acetyl), nitro and amino, and thelike.

As R¹, a phenyl group, a 2-fluorophenyl group, a 2-methylphenyl group, a2-fluoropyridin-3-yl group, a 3-fluoropyridin-4-yl group, a2-chloropyridin-3-yl group, a 6-chloropyridin-3-yl group, a4-methylpyridin-3-yl group, a 2-methylpyridin-3-yl group, a3-methylpyridin-2-yl group, a 2-trifluoromethylpyridin-3-yl group and a6′-chloro-2,3′-bipyridin-5-yl group are particularly preferable.

Preferably, R² is a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl,ethyl, n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g.,acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyletc.), a fluorine atom or a chlorine atom, and a hydrogen atom isparticularly preferable.

As R⁴, methyl or ethyl is preferable, and methyl is particularlypreferable.

The above-mentioned preferable embodiments of the substituents for R¹ toR⁴ may be optionally combined to achieve a preferable embodiment.

In a preferable embodiment, for example, R³ is a 5- or 6-memberedaromatic nitrogen-containing monocyclic heterocyclic group (e.g.,thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl and the like) or an imidazo[1,2-a]pyrimidinyl group, which areoptionally substituted by 1 to 3 substituents selected from (i) halogen(e.g., fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano,(iv) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), (vi) amino group optionallysubstituted by C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) and (vii)C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, tert-butoxycarbonyl etc.);

R¹ is [1] a C₆₋₁₄ aryl group (e.g., phenyl group) optionally substitutedby 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogenatom (e.g., fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C₁₋₆alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl etc.) optionally substituted by 1to 5 (preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) acetyl, (vi) C₃₋₇ cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.),(vii) C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.),(viii) a C₁₋₆ alkyl group substituted by 1 to 3 hydroxy (e.g.,hydroxymethyl, hydroxyethyl etc.), (ix) C₁₋₆ alkylthio (e.g.,methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, pentylthio, hexylthio etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (x) C₁₋₆ alkylsulfinyl (e.g.,methylsulfinyl, ethylsulfinyl etc.),[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy etc.) optionally substituted by 1 to 5 (preferably 1 to 3)halogens (e.g., fluorine, chlorine, bromine, iodine) and (v) acetyl,[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine), (ii) cyano, (iii) lower (specifically C₁₋₆) alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl etc.) optionally substituted by 1 to 5(preferably 1 to 3) halogens (e.g., fluorine, chlorine, bromine,iodine), (iv) C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), (v) acyl (e.g., acetyl), (vi) nitro and(vii) amino, or[4] a bipyridyl group optionally substituted by 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine, iodine);R² is a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g., acetyl,propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), afluorine atom or a chlorine atom, andR⁴ is methyl or ethyl is preferable,

In a particularly preferable embodiment,

R³ is a pyridyl group optionally substituted by 1 to 3 substituentsselected from (i) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) and (ii) C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxyetc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), R¹ is [1] a phenyl groupoptionally substituted by 1 to 5 (preferably 1 to 3) substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine),[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), or[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) lower (specifically C₁₋₆) alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine), andR² is a hydrogen atom, and R⁴ is methyl.

As the halogen atom for X₁, chlorine or bromine is preferable, andchlorine is more preferable.

As the leaving group for X, a halogen atom such as chlorine, bromine orthe like or a hydroxy group is preferable, and a halogen atom is morepreferable.

As the “optionally substituted hydrocarbon group” and “optionallysubstituted heterocyclic group” for R⁵, substituents similar to the“optionally substituted hydrocarbon group” and “optionally substitutedheterocyclic group” for the aforementioned R¹ are used. Of these,

[1] an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.),

[2] an optionally substituted C₆₋₁₄ aryl group (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl etc.), or

[3] an optionally substituted 5- to 10-membered aromatic heterocyclicgroup containing, besides carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom or an oxygen atom(e.g., 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-imidazolyl,4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl etc.) is preferablyused.

As the “acyl group” for R⁵, substituents similar to the “acyl group” forthe aforementioned R² are used. Of these,

[1] an optionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl etc.),

[2] an optionally substituted C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl,naphthalenecarbonyl etc.),

[3] an optionally substituted 5- or 6-membered heterocyclyl-carbonylgroup or a condensed heterocyclyl-carbonyl group thereof (e.g.,pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl and the like;imidazolylcarbonyl such as 2-, 4- or 5-imidazolylcarbonyl and the like;triazolylcarbonyl such as 1,2,3-triazol-4-ylcarbonyl,1,2,4-triazol-3-ylcarbonyl and the like; tetrazolylcarbonyl such as 1H-or 2H-tetrazol-5-ylcarbonyl and the like; furylcarbonyl such as 2- or3-furylcarbonyl and the like; thienylcarbonyl such as 2- or3-thienylcarbonyl and the like; oxazolylcarbonyl such as 2-, 4- or5-oxazolylcarbonyl and the like; isoxazolylcarbonyl such as 3-, 4- or5-isoxazolylcarbonyl and the like; oxadiazolylcarbonyl such as1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadiazol-3- or 5-ylcarbonyl,1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and thelike; thiazolylcarbonyl such as 2-, 4- or 5-thiazolylcarbonyl and thelike; isothiazolylcarbonyl such as 3-, 4- or 5-isothiazolylcarbonyl andthe like; thiadiazolylcarbonyl such as 1,2,3-thiadiazol-4- or5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5-ylcarbonyl, 1,2,5-thiadiazol-3-or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl and the like;pyrrolidinylcarbonyl such as 2- or 3-pyrrolidinylcarbonyl and the like;pyridylcarbonyl such as 2-, 3- or 4-pyridylcarbonyl and the like;pyridylcarbonyl wherein nitrogen atom is oxidized such as 2-, 3- or4-pyridyl-N-oxidocarbonyl and the like, or[4] an optionally substituted C₁₋₇ alkanoyl group (e.g., formyl; C₁₋₆alkyl-carbonylacetyl such as propionyl, butyryl, isobutyryl, pentanoyl,hexanoyl, heptanoyl and the like, etc.) is preferable.

Particularly, as the “acyl group” for R⁵, the above-mentioned [1], [2]or [3] is preferable.

In addition, as R⁵, a group represented by —S—R⁶ wherein R⁶ is asdefined above can be mentioned. As R⁶,

wherein the symbols in the formula are as defined above, is preferable,and

wherein the symbols in the formula are as defined above, is morepreferable.

As R⁵, a C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl) is particularlypreferable.

As n, 0 is preferable.

As m, 1 is preferable.

As R⁷, a cyano group or a C₁₋₄ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl) is preferable, and a cyano group is morepreferable.

As R⁸, a hydrogen atom, a C₁₋₆ alkyl group (e.g., methyl, ethyl,n-propyl, isobutyl etc.), a C₁₋₆ alkyl-carbonyl group (e.g., acetyl,propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl etc.), afluorine atom or a chlorine atom is preferable.

As R^(1a), a phenyl group having 1 to 5 (preferably 1 to 3) substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) or (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine) is preferable.

As R^(1b), the “optionally substituted hydrocarbon group” and“optionally substituted heterocyclic group” used for the aforementionedR¹ can be mentioned. Of these, an optionally substituted C₆₋₁₄ arylgroup (e.g., phenyl, 1-naphthyl, 2-naphthyl), an optionally substituted3- to 8-membered heterocyclic group (e.g., thienyl, pyridyl) or anoptionally substituted C₁₋₆ alkyl group (e.g., methyl) is preferable.

More preferable examples of R^(1b) include

[1] a phenyl group optionally substituted by 1 to 5 (preferably 1 to 3)substituents selected from (i) a halogen atom (e.g., fluorine, chlorine,bromine, iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.)optionally substituted by 1 to 5 (preferably 1 to 3) halogens (e.g.,fluorine, chlorine, bromine, iodine),[2] a thienyl group optionally substituted by 1 to 3 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 5 (preferably 1 to 3) halogens (e.g., fluorine,chlorine, bromine, iodine), or[3] a pyridyl group optionally substituted by 1 to 4 substituentsselected from (i) a halogen atom (e.g., fluorine, chlorine, bromine,iodine) and (ii) lower (specifically C₁₋₆) alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyletc.) optionally substituted by 1 to 5 (preferably 1 to 3) halogens(e.g., fluorine, chlorine, bromine, iodine) is preferable.

Preferable examples of compound (VIII), which is an object compound,include1-{5-(2-fluorophenyl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamineor a salt thereof,1-[4-fluoro-5-phenyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof,N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamineor a salt thereof,1-[5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof,1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof,N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanamineor a salt thereof, and the like.

The production method of the present invention is explained in detail inthe following.

As salts of compounds (I)-(XVII) in reaction wherein metal salt,ammonium salt, salts with organic bases, salts with inorganic bases,salts with organic acids, salts with basic or acidic amino acids and thelike can be mentioned. Preferable examples of metal salt include alkalimetal salts such as sodium salt, potassium salt and the like; alkalineearth metal salts such as calcium salt, magnesium salt, barium salt andthe like; aluminum salt and the like. Preferable examples of the saltwith organic base include a salt with trimethylamine, triethylamine,pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of thesalt with inorganic acid include a salt with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferable examples of the salt with organic acid include a saltwith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of the saltwith basic amino acid include a salt with arginine, lysine, ornithineand the like. Preferable examples of the salt with acidic amino acidinclude a salt with aspartic acid, glutamic acid and the like.

While the compounds obtained in respective steps can be used for thenext reaction in the form of a reaction mixture or a crude product, theycan also be easily isolated and purified from the reaction mixture by aknown separation and purification means, such as recrystallization,distillation, chromatography and the like.

(Method 1)

wherein each symbol is as defined above.Step 1

Compound (II) or a salt thereof can be produced by cyclizing compound(I) or a salt thereof in the presence of hydrogen halide.

This reaction can be performed according to the method described inJP-A-6-9554 and the like, or a method analogous thereto.

Compound (I) or a salt thereof can be produced according to, forexample, the method described in JP-A-6-9554 and the like, or a methodanalogous thereto.

Step 2

Compound (III) or a salt thereof can be produced by subjecting compound(II) or a salt thereof to dehalogenation.

As the dehalogenation, a method of catalytic hydrogenation can bementioned.

The catalytic hydrogenation can be performed in the presence of ahydrogen source and a metal catalyst. Examples of the metal catalystinclude palladium catalyst (e.g., palladium carbon, palladium hydroxidecarbon, palladium oxide and the like), nickel catalyst (e.g.,Raney-nickel and the like), platinum catalyst (e.g., platinum oxide,platinum carbon and the like), rhodium catalyst (e.g., rhodium carbonand the like), cobalt catalyst (e.g., Raney-cobalt and the like) and thelike. Of these, palladium carbon or Raney-nickel is preferable. Theamount of the metal catalyst to be used is about 0.001 to about 10 mol,preferably about 0.001 to about 5 mol, per 1 mol of compound (II).

Examples of the hydrogen source include hydrogen gas, formic acid,ammonium formate, triethylammonium formate, sodium phosphinate,hydrazine and the like. When a hydrogen source other than hydrogen gasis used, a compound of a hydrogen source is used in about 1 to about 10mol, preferably about 1 to about 5 mol, per 1 mol of compound (II).

The dehalogenation is preferably performed in the presence of a base. Asthe base, for example, inorganic bases such as sodium hydride, sodiumhydroxide, potassium hydroxide and the like, basic salts such as sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide,potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as diisopropylethylamine, triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-N,N-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, and the like can be mentioned.Preferred are tertiary amines such as diisopropylethylamine and thelike. The amount of the base to be used is about 1 to about 10 mol,preferably about 1 to about 5 mol, per 1 mol of compound (II).

The dehalogenation is generally performed in a solvent inert to thereaction. Examples of such solvent include alcohols (e.g., methanol,ethanol, propanol, butanol and the like), hydrocarbons (e.g., benzene,toluene, xylene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), esters (e.g., ethyl acetate andthe like), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamideand the like), carboxylic acids (e.g., acetic acid and the like), waterand a mixture thereof. The amount of the solvent to be used is generallyabout 1 to about 100 ml, preferably about 1 to about 50 ml, per 1 g ofcompound (II).

The hydrogen pressure under which the reaction is performed is generallyabout 0 to about 10 atm, preferably about 0 to about 5 atm. The reactiontemperature is generally about −50° C. to about 100° C., preferablyabout −20° C. to about 50° C. The reaction time is generally about 0.5to about 24 hr, preferably about 0.5 to about 10 hr.

Step 3

Compound (IV) or a salt thereof can be produced by reducing compound(III) or a salt thereof and hydrolyzing the reduced product.

As the reduction, a method using metal hydride and a method usingcatalytic hydrogenation can be mentioned.

Examples of the metal hydride include boron reagent (e.g., sodiumborohydride, lithium borohydride, zinc borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydrideand the like), aluminum reagent (e.g., diisobutylaluminum hydride,aluminum hydride, lithium aluminum hydride and the like), borane complex(e.g., borane-THF complex, borane-dimethylsulfide, borane-pyridine andthe like), catechol borane and the like. The amount of the metal hydrideto be used is, for example, about 0.2 to about 10 mol, preferably about0.2 to about 5 mol, per 1 mol of compound (III).

The reduction reaction by metal hydride is generally performed in asolvent inert to the reaction. Examples of such solvent include aromatichydrocarbons (e.g., toluene, xylene, chlorobenzene and the like),aliphatic hydrocarbons (e.g., heptane, hexane and the like), halogenatedhydrocarbons (e.g., chloroform, dichloromethane and the like), ethers(e.g., diethyl ether, tetrahydrofuran, dioxane and the like), and amixture thereof. The amount of the solvent to be used is generally about1 to about 100 ml, preferably about 1 to about 50 ml, per 1 g ofcompound (III).

The reaction temperature is generally about −100° C. to about 100° C.,preferably about −70° C. to about 50° C. The reaction time is generallyabout 0.5 to about 24 hr, preferably about 0.5 hr to about 5 hr.

The catalytic hydrogenation can be performed in the presence of ahydrogen source and a metal catalyst. Examples of the metal catalystinclude palladium catalyst (e.g., palladium carbon, palladium hydroxidecarbon, palladium oxide and the like), nickel catalyst (e.g.,Raney-nickel and the like), platinum catalyst (e.g., platinum oxide,platinum carbon and the like), rhodium catalyst (e.g., rhodium carbonand the like) and the like. Of these, palladium carbon or Raney-nickelis preferable. The amount of the metal catalyst to be used is about0.0001 to about 10 mol, preferably about 0.001 to about 5 mol, per 1 molof compound (III), or about 0.1 g to about 10 g, preferably about 0.3 gto about 5 g, per 1 g of compound (III).

Examples of the hydrogen source include hydrogen gas, formic acid,ammonium formate, triethylammonium formate, sodium phosphinate,hydrazine and the like. When a hydrogen source other than hydrogen gasis used, a compound of a hydrogen source is used in about 1 to about 100mol, preferably about 1 to about 50 mol, more preferably about 1 toabout 10 mol, for example, about 1 to about 5 mol, per 1 mol of compound(III).

The catalytic hydrogenation is generally performed in a solvent inert tothe reaction. Examples of such solvent include alcohols (e.g., methanol,ethanol, propanol, butanol and the like), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene and the like), halogenatedhydrocarbons (e.g., dichloromethane, chloroform and the like), ethers(e.g., diethyl ether, dioxane, tetrahydrofuran and the like), esters(e.g., ethyl acetate and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like), carboxylic acids (e.g., acetic acidand the like), water and a mixture thereof. The amount of the solvent tobe used is generally about 1 to about 1000 ml, preferably about 1 toabout 100 ml, per 1 g of compound (III).

The hydrogen pressure under which the reaction is performed is generallyabout 0 to about 10 atm, preferably about 0 to about 5 atm. The reactiontemperature is generally about −50° C. to about 100° C., preferablyabout −20° C. to about 50° C. The reaction time is generally about 1 toabout 100 hr, preferably about 1 to about 24 hr, for example, about 1 toabout 10 hr.

The hydrolysis can be performed in the presence of an acid or a base.Examples of the acid include inorganic acid (hydrochloric acid, sulfuricacid, nitric acid, phosphoric acid, boric acid and the like), organiccarboxylic acid (formic acid, acetic acid, propionic acid and the like),organic sulfonic acid (methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, trifluoromethanesulfonic acid and the like) andthe like. The amount of the acid to be used is about 0.1 to about 10mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (III).Examples of the base include inorganic bases such as sodium hydroxide,potassium hydroxide and the like, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydrogen carbonate etc.,and the like. The amount of the base to be used is about 0.1 to about 10mol, preferably about 0.1 to about 5 mol, per 1 mol of compound (III).

The hydrolysis is advantageously performed using a solvent inert to thereaction. While such solvent is not particularly limited as long as thereaction proceeds, alcohols (e.g., methanol, ethanol, propanol, butanoland the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene,chlorobenzene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide and the like), carboxylicacids (e.g., acetic acid and the like), water and a mixture thereof canbe mentioned. The amount of the solvent to be used is generally about 1to about 100 ml, preferably about 1 to about 50 ml, per 1 g of compound(III).

The reaction temperature is generally about −20° C. to about 100° C.,preferably about 0° C. to about 50° C. The reaction time is generallyabout 1 to about 48 hr, preferably about 1 to about 24 hr.

Step 4

Compound (VI) or a salt thereof can be produced by subjecting compound(IV) or a salt thereof to a reaction with compound (V) or a saltthereof.

The amount of compound (V) to be used is preferably about 1 to about 10mol, more preferably about 1 to about 5 mol, per 1 mol of compound (IV).

This reaction is advantageously performed using a solvent inert to thereaction. While such solvent is not particularly limited as long as thereaction proceeds, alcohols (e.g., methanol, ethanol, propanol, butanoland the like), aromatic hydrocarbons (e.g., benzene, toluene, xylene,chlorobenzene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), esters (e.g., ethyl acetate andthe like), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamideand the like), acid nitriles (e.g., acetonitrile, propionitrile and thelike), water and a mixture thereof can be mentioned. The amount of thesolvent to be used is generally 1 to 100 ml, preferably 1 to 50 ml, per1 g of compound (IV).

This reaction is preferably performed in the presence of a base.Examples of the base include inorganic bases such as sodium hydride,sodium hydroxide, potassium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide,potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as diisopropylethylamine, triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-N,N-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, and a mixture thereof and the like. Theamount of the base to be used is about 0.01 to about 10 mol, preferablyabout 0.1 to about 5 mol, per 1 mol of compound (IV).

The reaction can also be carried out in the co-presence of crown ether.As the crown ether, for example, 15-crown-5-ether, 18-crown-6-ether andthe like can be mentioned. The amount of the crown ether to be used isabout 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol ofcompound (IV).

The reaction time is generally about 30 min to about 24 hr, preferablyabout 30 min to about 8 hr. The reaction temperature is generally about0° C. to about 100° C., preferably about 10° C. to about 50° C.

Step 5

Compound (VIII) or a salt thereof can be produced by reacting compound(VI) or a salt thereof with compound (VII) or a salt thereof, andreducing the imine formed. Alternatively, compound (VIII) or a saltthereof can be produced without isolating the imine formed by performingthe reaction of compound (VI) or a salt thereof with compound (VII) or asalt thereof in the presence of a reducing agent.

This reaction can be performed according to the conventional reactionconditions known as reductive amination reaction. For example, thereaction can be performed according to the method described in JikkenKagaku Koza (Courses in Experimental Chemistry), vol. 14-III, pages1380-1385 (Maruzen Co., Ltd.).

The amount of compound (VII) to be used is preferably about 1 to about10 mol, more preferably about 1 to about 5 mol, per 1 mol of compound(VI).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, and alcohols (e.g., methanol, ethanol, propanol,butanol and the like), aromatic hydrocarbons (e.g., benzene, toluene,xylene, chlorobenzene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), esters (e.g., ethyl acetate andthe like), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamideand the like), water and a mixture thereof can be mentioned. The amountof the solvent to be used is generally 1 to 100 ml, preferably 1 to 50ml, per 1 g of compound (VI).

The reaction time is generally about 0.5 to about 24 hr, preferablyabout 0.5 to about 10 hr. The reaction temperature is generally about−50° C. to about 100° C., preferably about −10° C. to about 50° C.

As a reducing agent, sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride and the like can be used. The amount of thereducing agent to be used is preferably about 0.2 to about 10 mol, morepreferably about 0.2 to about 5 mol, per 1 mol of compound (VI).

The reduction can also be performed by catalytic hydrogenation.

The catalytic hydrogenation can be performed in the presence of ahydrogen source and a metal catalyst. Examples of the metal catalystinclude palladium catalyst (e.g., palladium carbon, palladium hydroxidecarbon, palladium oxide and the like), nickel catalyst (e.g.,Raney-nickel and the like), platinum catalyst (e.g., platinum oxide,platinum carbon and the like), rhodium catalyst (e.g., rhodium carbonand the like), cobalt catalyst (e.g., Raney-cobalt and the like) and thelike. Of these, palladium carbon or Raney-nickel is preferable. Theamount of the metal catalyst to be used is about 0.01 to about 10 mol,preferably about 0.01 to about 5 mol, per 1 mol of compound (VI).

As a hydrogen source, hydrogen gas, formic acid, ammonium formate,triethylammonium formate, sodium phosphinate, hydrazine and the like canbe mentioned. When a hydrogen source other than hydrogen gas is used, acompound of a hydrogen source is used in about 1 to about 100 mol,preferably about 1 to about 50 mol, more preferably about 1 to about 10mol, for example, about 1 to about 5 mol, per 1 mol of compound (VI).

The reduction is advantageously performed using a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds, and alcohols (e.g., methanol, ethanol, propanol,butanol and the like), hydrocarbons (e.g., benzene, toluene, xylene andthe like), halogenated hydrocarbons (e.g., dichloromethane, chloroformand the like), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran andthe like), esters (e.g., ethyl acetate and the like), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide and the like), water and amixture thereof can be mentioned. The amount of the solvent to be usedis generally 1 to 100 ml, preferably 1 to 50 ml, per 1 g of compound(VI).

The reaction time is generally about 0.5 to about 24 hr, preferablyabout 0.5 to about 10 hr. The reaction temperature is generally about−50° C. to about 100° C., preferably about −20° C. to about 50° C.

(Method 2)

wherein each symbol is as defined above.Step 6

Compound (X) or a salt thereof can be produced by reacting compound (I)or a salt thereof with compound (IX) or a salt thereof.

As compound (IX) or a salt thereof, thiocarboxylic acid (e.g.,thiobenzoic acid), sodium thiomethoxide, a thiol compound represented byR⁵SH (R⁵ is as defined above) and the like can be used. The amount ofcompound (IX) to be used is preferably about 1 to about 10 mol, morepreferably about 1 to about 5 mol, per 1 mol of compound (I).

When sodium thiomethoxide is used as compound (IX) or a salt thereof,the reaction is preferably performed in the presence of an acid. As theacid, carboxylic acid such as acetic acid and the like, and the like canbe mentioned. Preferred is acetic acid. The amount of the acid to beused is about 0.1 to about 10 mol, preferably about 1 to about 5 mol,per 1 mol of compound (I).

When thiocarboxylic acid or a thiol compound is used as compound (IX) ora salt thereof, the reaction is preferably performed in the presence ofa base. Examples of the base include inorganic bases such as sodiumhydride, sodium hydroxide, potassium hydroxide and the like, basic saltssuch as sodium carbonate, potassium carbonate, cesium carbonate, sodiumhydrogen carbonate and the like, metal bases such as potassium ethoxide,potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as diisopropylethylamine, triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-N,N-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, and the like. Preferred are tertiaryamines such as triethylamine, diisopropylethylamine and the like. Theamount of the base to be used is about 0.05 to about 10 mol, preferablyabout 0.1 to about 5 mol, per 1 mol of compound (I).

This reaction is advantageously carried out using a solvent inert to thereaction. While the solvent is not particularly limited as long as thereaction proceeds, solvents such as alcohols (e.g., methanol, ethanol,propanol, butanol and the like), aromatic hydrocarbons (e.g., benzene,toluene, xylene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform, chlorobenzene and the like), ethers (e.g.,diethyl ether, dioxane, tetrahydrofuran and the like), esters (e.g.,ethyl acetate and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like), ketones (e.g., acetone, methylethyl ketone and the like) and the like and a mixed solvent thereof andthe like are preferable. The amount of the solvent to be used isgenerally 1 to 50 ml, preferably 1 to 20 ml, per 1 g of compound (I).

The reaction time is generally about 1 to about 50 hr, preferably about1 to about 20 hr. The reaction temperature is generally about 0° C. toabout 150° C., preferably about 15° C. to about 100° C.

Step 7

Compound (III) or a salt thereof can be produced by subjecting compound(X) or a salt thereof to a desulfurization reaction.

The desulfurization reaction can be performed by reaction with metals(e.g., Raney-nickel) or reaction with a combination of sodiumborohydride and a metal salt (e.g., nickel chloride).

The desulfurization reaction is generally performed in a solvent inertto the reaction. Examples of such solvent include alcohols (e.g.,methanol, ethanol, propanol, butanol and the like), aromatichydrocarbons (e.g., benzene, toluene, xylene, chlorobenzene and thelike), halogenated hydrocarbons (e.g., dichloromethane, chloroform andthe like), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran and thelike), esters (e.g., ethyl acetate and the like), amides (e.g.,N,N-dimethylformamide, N,N-dimethylacetamide and the like), carboxylicacids (e.g., acetic acid and the like), water and a mixture thereof. Theamount of the solvent to be used is generally about 1 to about 50 ml,preferably about 1 to about 20 ml, per 1 g of compound (X).

The desulfurization reaction using Raney-nickel is preferably performedin the presence of a base. As the base, secondary amine such asmorpholine and the like can be mentioned. The amount of the base to beused is about 0.1 to about 10 mol, preferably about 0.5 to about 5 mol,per 1 mol of compound (X).

The reaction time is generally about 1 to about 50 hr, preferably about1 to about 20 hr. The reaction temperature is generally about 0° C. toabout 200° C., preferably about 20° C. to about 150° C.

Step 14

Compound (XVII) or a salt thereof can be produced by reacting compound(III) or a salt thereof with compound (V) or a salt thereof, as in step4.

Step 15

Compound (VI) or a salt thereof can be produced by reducing compound(XVII) or a salt thereof, followed by hydrolysis, as in step 3.

Then, the obtained compound (VI) or a salt thereof is reacted withcompound (VII) or a salt thereof, in the same manner as in theaforementioned step 5, whereby compound (VIII) or a salt thereof can beproduced.

(Method 3)

wherein each symbol is as defined above.Step 8

Compound (XI) or a salt thereof can be produced by reacting compound (I)or a salt thereof with a sulfur reagent.

Examples of the sulfur reagent include hydrogen sulfide, thioaceticacid, thiouric acid, thioacetamide and the like. The amount of thesulfur reagent to be used is about 1 to about 10 mol, preferably about 1to about 5 mol, per 1 mol of compound (I).

This reaction is advantageously performed using a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds, and solvents such as alcohols (e.g., methanol,ethanol, propanol, butanol and the like), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene and the like), halogenatedhydrocarbons (e.g., dichloromethane, chloroform and the like), ethers(e.g., diethyl ether, dioxane, tetrahydrofuran and the like), esters(e.g., ethyl acetate and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like), ketones (e.g., acetone, methylethyl ketone and the like) and the like and a mixed solvent thereof, andthe like are preferable. The amount of the solvent to be used isgenerally 1 to 50 ml, preferably 1 to 20 ml, per 1 g of compound (I).

This reaction is preferably performed in the presence of a base.Examples of the base include inorganic bases such as sodium hydride,sodium hydroxide, potassium hydroxide and the like, basic salts such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate and the like, metal bases such as potassium ethoxide,potassium tert-butoxide, sodium methoxide, sodium ethoxide and the like,aromatic amines such as pyridine, lutidine and the like, tertiary aminessuch as diisopropylethylamine, triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-N,N-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like, and the like. Preferred are tertiaryamines such as triethylamine, diisopropylethylamine and the like. Theamount of the base to be used is about 0.1 to about 10 mol, preferablyabout 0.1 to about 5 mol, per 1 mol of compound (I).

The reaction time is generally about 1 to about 50 hr, preferably about1 to about 20 hr. The reaction temperature is generally about 0° C. toabout 150° C., preferably about 0° C. to about 100° C.

Step 9

Compound (III) or a salt thereof can be produced by subjecting compound(XI) or a salt thereof to a desulfurization reaction.

The desulfurization reaction can be performed by a method similar toMethod 2, step 7.

Compound (VIII) or a salt thereof can be produced from compound (III) ora salt thereof by a method similar to the aforementioned step 14, step15 and step 5.

(Method 4)

wherein each symbol is as defined above.Step 10

Compound (XIII) or a salt thereof can be produced by subjecting compound(XII) or a salt thereof to a reduction reaction.

The reduction reaction can be performed by a catalytic hydrogenation andthe like.

The catalytic hydrogenation can be performed in the presence of ahydrogen source and a metal catalyst. Examples of the metal catalystinclude palladium catalyst (e.g., palladium carbon, palladium hydroxidecarbon, palladium oxide, palladium supported by carrier such as ceramic,cellulose, resin and the like, and the like), nickel catalyst (e.g.,Raney-nickel and the like), platinum catalyst (e.g., platinum oxide,platinum carbon and the like), rhodium catalyst (e.g., rhodium carbonand the like), cobalt catalyst (Raney-cobalt and the like) and the like.Of these, palladium carbon or Raney-nickel is preferable. The amount ofthe metal catalyst to be used is about 0.001 to about 10 mol, preferablyabout 0.01 to about 5 mol, per 1 mol of compound (XII).

As the hydrogen source, hydrogen gas, formic acid, ammonium formate,triethylammonium formate, sodium phosphinate, hydrazine and the like canbe mentioned. When a hydrogen source other than hydrogen gas is used, acompound of a hydrogen source is used in about 0.1 to about 100 mol,preferably about 0.1 to about 50 mol, more preferably about 1 to about50 mol, particularly preferably about 1 to about 5 mol, per 1 mol ofcompound (XII).

The catalytic hydrogenation is generally performed in a solvent inert tothe reaction. Examples of such solvent include alcohols (e.g., methanol,ethanol, propanol, butanol and the like), aromatic hydrocarbons (e.g.,benzene, toluene, xylene, chlorobenzene and the like), halogenatedhydrocarbons (e.g., dichloromethane, chloroform and the like), ethers(e.g., diethyl ether, dioxane, tetrahydrofuran and the like), esters(e.g., ethyl acetate and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide and the like), carboxylic acids (e.g., acetic acidand the like), water and a mixture thereof. The amount of the solvent tobe used is generally about 1 to about 1000 ml, preferably about 3 toabout 100 ml, per 1 g of compound (XII).

The hydrogen pressure under which the reaction is performed is generallyabout 0 to about 10 atm, preferably about 0 to about 5 atm. The reactiontemperature is generally about −10° C. to about 200° C., preferablyabout 5° C. to about 80° C. The reaction time is generally about 0.5 toabout 48 hr, preferably about 1 to about 12 hr.

Compound (XII) or a salt thereof can be produced according to the methoddescribed in, for example, JP-A-6-9554 and the like, or a methodanalogous thereto.

Step 11

Compound (XIV) or a salt thereof can be produced by cyclizing compound(XIII) or a salt thereof.

The cyclization reaction is preferably performed under acidicconditions. As the acid to be used, organic carboxylic acid (formicacid, acetic acid, propionic acid, trifluoroacetic acid, citric acid andthe like), organic sulfonic acid (methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and thelike), inorganic acid (hydrochloric acid, sulfuric acid, nitric acid andthe like) and the like can be mentioned. The amount of the acid to beused is about 0.01 to about 100 mol, preferably about 0.1 to about 50mol, per 1 mol of compound (XIII).

This reaction is advantageously performed using a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds, and alcohols (e.g., methanol, ethanol, propanol,butanol and the like), aromatic hydrocarbons (e.g., benzene, toluene,xylene, chlorobenzene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), esters (e.g., ethyl acetate andthe like), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamideand the like), carboxylic acids (e.g., acetic acid and the like), waterand a mixture thereof can be mentioned. The amount of the solvent to beused is generally about 1 to about 1000 ml, preferably about 3 to about100 ml, per 1 g of compound (XIII).

The reaction time is generally about 0.1 to about 48 hr, preferablyabout 0.5 to about 6 hr. The reaction temperature is generally about−10° C. to about 100° C., preferably about 25° C. to about 60° C.

Step 12

Compound (XIV) or a salt thereof can also be obtained by subjectingcompound (XIII) or a salt thereof obtained in the aforementioned step10, without isolation, to a cyclization reaction in the next step 11.

For example, the catalyst is filtered off from the reaction mixtureobtained in step 10, the filtrate is concentrated as necessary, and anacid is added to cause reaction, whereby compound (XIV) or a saltthereof can be obtained. The kind and amount of the reaction solventsand reagents, reaction time and reaction temperature are similar tothose in step 10 and step 11.

Compound (VIII) or a salt thereof can be produced from compound (XIV) ora salt thereof by the aforementioned method of converting compound (III)to compound (VIII) or a method known per se.

(Method 5)

wherein each symbol is as defined above.Step 13

Compound (XVI) or a salt thereof can be produced by cyclizing compound(XV) or a salt thereof in the presence of a reducing agent.

As a reducing agent, a hydrogen source and a metal catalyst can be used.Examples of the metal catalyst include palladium catalyst (e.g.,palladium carbon, palladium hydroxide carbon, palladium oxide, orpalladium supported by carrier such as ceramic, cellulose, resin and thelike, and the like), nickel catalyst (e.g., Raney-nickel and the like),platinum catalyst (e.g., platinum oxide, platinum carbon and the like),rhodium catalyst (e.g., rhodium carbon and the like), cobalt catalyst(Raney-cobalt and the like) and the like. Of these, palladium carbon orRaney-nickel is preferable. The amount of the metal catalyst to be usedis about 0.001 to about 100 mol, preferably about 0.01 to about 10 mol,per 1 mol of compound (XV).

As a hydrogen source, hydrogen gas, formic acid, ammonium formate,triethylammonium formate, sodium phosphinate, hydrazine and the like canbe mentioned. When a hydrogen source other than hydrogen gas is used, acompound of a hydrogen source is used in about 1 to about 1000 mol,preferably about 3 to about 30 mol, per 1 mol of compound (XV) Thisreaction is advantageously performed using a solvent inert to thereaction. Such solvent is not particularly limited as long as thereaction proceeds, and alcohols (e.g., methanol, ethanol, propanol,butanol and the like), aromatic hydrocarbons (e.g., benzene, toluene,xylene, chlorobenzene and the like), halogenated hydrocarbons (e.g.,dichloromethane, chloroform and the like), ethers (e.g., diethyl ether,dioxane, tetrahydrofuran and the like), esters (e.g., ethyl acetate andthe like), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamideand the like), carboxylic acids (e.g., acetic acid and the like), waterand a mixture thereof can be mentioned. The amount of the solvent to beused is generally about 1 to about 1000 ml, preferably about 3 to about100 ml, per 1 g of compound (XV).

The cyclization reaction is preferably performed in the presence of anacid. Examples of the acid include organic carboxylic acid (formic acid,acetic acid, propionic acid, trifluoroacetic acid, citric acid and thelike), organic sulfonic acid (methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and thelike), inorganic acid (hydrochloric acid, sulfuric acid, nitric acid andthe like) and the like. The amount of the acid to be used is about 0.01to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol ofcompound (XV).

The reaction time is generally about 0.5 to about 48 hr, preferablyabout 1 to about 12 hr. The reaction temperature is generally about −10°C. to about 100° C., preferably about 10° C. to about 50° C.

Compound (VIII) or a salt thereof can be produced from compound (XVI) ora salt thereof by the aforementioned method of converting compound (IV)to compound (VIII) or a method known per se.

Of the 3-cyanopyrrole compounds used for the production method of thepresent invention, a compound represented by the formula

wherein R^(1a) is an aryl group having substituent(s), or a saltthereof, and a compound represented by the formula

wherein R^(1b) is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R⁵ is an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an acyl group or a group represented by —S—R⁶ (R⁶ is anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group), and n is 0, 1 or 2 (excluding2,2′-dithiobis(5-methyl-1H-pyrrole-3-carbonitrile),2,2′-dithiobis(5-phenyl-1H-pyrrole-3-carbonitrile),2,2′-dithiobis[5-(4-chlorophenyl)-1H-pyrrole-3-carbonitrile],2,2′-dithiobis[5-(4-methylphenyl)-1H-pyrrole-3-carbonitrile] and2,2′-dithiobis[5-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile]) or a saltthereof are novel compounds.

In a compound represented by the formula

wherein each symbol is as defined above, when R⁵ is —S—R⁶ (R⁶ is asdefined above), a preferable embodiment of R⁶ is

wherein R^(1′) is as defined for the aforementioned R¹, preferably [1] aphenyl group optionally substituted by 1 to 5 substituents selected from(i) a halogen atom and (ii) C₁₋₆ alkyl optionally substituted by 1 to 5halogen atoms, or [2] a pyridyl group optionally substituted by 1 to 4substituents selected from lower (C₁₋₆) alkyl, a halogen atom, alkoxy(C₁₋₆ alkoxy), cyano, acyl (e.g., acetyl), nitro and amino, which is apreferable example of R¹, and further preferably [1] a phenyl grouphaving one substituent selected from (i) a halogen atom and (ii) C₁₋₆alkyl optionally substituted by 1 to 5 halogen atoms, at the 2-position,or [2] a pyridyl group optionally substituted 1 to 4 substituentsselected from lower (C₁₋₆)alkyl, a halogen atom, alkoxy (C₁₋₆ alkoxy),cyano, acyl (e.g., acetyl), nitro and amino, and R² is as defined above,and

wherein the symbol in the formula is as defined above, is morepreferable.

As R^(1′), 2-position substituted phenyl (e.g., 2-fluorophenyl,2-methylphenyl etc.) is particularly preferable.

R⁵ in the formula

wherein each symbol is as defined above, is a preferable embodiment ofthe aforementioned R⁵. Particularly, R⁵ is[1] a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc.) optionallysubstituted by 1 to 3 substituents selected from (i) a halogen atom(e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.),(ii) nitro, (iii) amino and (iv) carboxyl,[2] a C₆₋₁₄ aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.) optionallysubstituted by 1 to 3 substituents selected from (i) a halogen atom(e.g., fluorine atom, chlorine atom, bromine atom, iodine atom etc.),(ii) nitro, (iii) amino and (iv) carboxyl,[3] a heterocyclic group (e.g., pyridyl (e.g., 2-, 3- or 4-pyridyl)etc.),[4] an optionally substituted C₆₋₁₄ aryl-carbonyl group (e.g., benzoyl,naphthalenecarbonyl etc.), or[5] a group represented by the formula

wherein the symbols in the formula are as defined above.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples and Examples, which are not to beconstrued as limitative.

In the following Reference Examples and Examples, the “room temperature”generally means about 10° C. to about 35° C., but it is not particularlystrictly limited. The mixing ratio of liquids shows a volume ratio.Unless otherwise specified, “%” means weight %. The yield is in mol/mol%. Silica gel column chromatography was performed using silica gel 60(0.063-0.200 mm) manufactured by MERCK or Fuji Silysia Chemical Ltd.Chromatorex (trade name) NH (described as basic silica gel columnchromatography). The melting point was measured using Yanagimoto tracemelting point measurement apparatus or

Büchi

trace melting point measurement apparatus (B-545), and uncorrected. For¹H-NMR spectrum, tetramethylsilane was used as the internal standard,and Bruker DPX-300 (300 MHz) or Bruker AVANCEIII500 (500 MHz) were usedfor the measurement.

The following abbreviations in Examples and Reference Examples mean asfollows.

s: singlet, d: doublet, dd: double doublet, dt: double triplet, t:triplet, q: quartet, m: multiplet, br: broad, brs: broad singlet, J:coupling constant, Hz: Hertz, THF: tetrahydrofuran, HPLC: highperformance liquid chromatography.

Reference Example 12-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (135.0 g, 667.7 mmol)and ethyl acetate (540 ml) were added in a four neck flask, 4 Nhydrochloric acid-ethyl acetate (417 ml, 1.67 mol) was added, and themixture was stirred at the internal temperature of 40-50° C. for 2.5 hr.Ethyl acetate (270 ml) was added, and the mixture was stirred at theinternal temperature of 70-80° C. for 2 hr. The internal temperature wascooled to 50° C., and seed crystals (68 mg) of the title compound wereadded. The mixture was continuously stirred at the internal temperatureof 20-30° C. for 0.5 hr and at the internal temperature of 0-10° C. for1 hr. The precipitated crystals were collected by filtration, washedwith cold ethyl acetate (270 ml), and dried under reduced pressure at50° C. until a constant weight was reached to give the title compound(73.9 g, yield 50.2%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.91 (d, J=2.0 Hz, 1H), 7.27-7.42 (m,3H), 7.70-7.75 (m, 1H), 13.05 (brs, 1H).

elemental analysis (C₁₁H₆N₂ClF)

Calculated: C:59.88, H:2.74, N:12.70, Cl:16.06, F:8.61.

Found: C:59.74, H:2.75, N:12.75, Cl:16.02, F:8.51.

melting point 218-220° C.

Reference Example 22-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (5.0 g, 24.7 mmol) andTHF (50 ml) were added in a four neck flask, and then hydrochloric acidgas (5 g, 137 mmol) was added. The mixture was stirred at the internaltemperature of 55-65° C. for 3 hr. Acetonitrile (20 ml) was added, andthe mixture was concentrated to about 17.5 g. Acetonitrile (20 ml) wasadded, and the mixture was concentrated again to about 17.5 g.Acetonitrile (17.5 ml) was added, and water (15 ml) was added dropwiseat the internal temperature of 55-65° C. The mixture was continuouslystirred at the internal temperature of 55-65° C. for 1 hr and at theinternal temperature of 20-30° C. for 1 hr. The precipitated crystalswere collected by filtration, washed with a cold mixed solution ofacetonitrile and water (1:1, 10 ml), and dried under reduced pressure at50° C. until a constant weight was reached to give the title compound(4.59 g, yield 84.2%).

¹H-NMR (500 MHz, CDCl₃) δ(ppm): 6.77-6.78 (m, 1H), 7.14-7.23 (m, 2H),7.28-7.31 (m, 1H), 7.51-7.55 (m, 1H), 9.21 (brs, 1H).

Reference Example 3 [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile

2-Methylacetophenone (466 mmol, 62.5 g) and ethyl acetate (375 ml) wereadded in a four neck flask. The internal temperature was maintained at25±5° C., and a solution of bromine (489 mmol, 78.1 g) in ethyl acetate(180 ml) was slowly added dropwise. After the completion of the dropwiseaddition, the mixture was stirred at the same temperature for 1 hr. Tapwater (375 ml) was added dropwise at the internal temperature of notmore than 35° C., sodium sulfite (89.4 mmol, 11.3 g) was added, and themixture was stirred at room temperature for 1 hr. The organic layer wasseparated, and washed successively with 3% aqueous sodium hydrogencarbonate solution (375 ml) and 10% brine (375 ml) to give a solution of2-bromo-1-(2-methylphenyl)ethanone in ethyl acetate.

The solution of 2-bromo-1-(2-methylphenyl)ethanone in ethyl acetateobtained above was cooled, malononitrile (466 mmol, 30.8 g) was added atthe internal temperature of 5±5° C., and the dropping funnel was washedwith ethyl acetate (40 ml) and the washing was added.Diisopropylethylamine (513 mmol, 87.8 ml) was added dropwise at theinternal temperature of 10±5° C. After the dropwise addition, themixture was stirred at the internal temperature of 5±5° C. for 2 hr. Tapwater (375 ml) was added, and the mixture was partitioned at roomtemperature. The aqueous layer was further extracted with ethyl acetate(188 ml). The organic layers were combined, and washed with a mixture of1 N hydrochloric acid (18.8 ml) and 10% brine (188 ml), and 10% brine(188 ml) in this order. The organic layer was concentrated to about halfamount under reduced pressure. Methanol (375 ml) was added to theconcentrate, and the mixture was concentrated to about 239 g. Thisoperation was performed 3 times in total. Water (27.7 ml) was addedwhile stirring the concentrate with heating to 55±5° C., and the mixturewas stirred at the same temperature for 1 hr. The reaction mixture wasgradually cooled to not more than 30° C., further cooled to the internaltemperature of 5±5° C., and stirred for 1 hr. The precipitated crystalswere collected by filtration, cooled, and washed with a mixture ofmethanol (24 ml) and water (3.6 ml). The wet crystals were dried underreduced pressure at 50° C. to give the title compound (70.3 g, yield76%).

melting point 92.0-93.0° C.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.47 (s, 3H), 4.01 (d, J=6.04 Hz, 2H),5.08 (t, J=6.04 Hz, 1H), 7.33-7.40 (m, 2H), 7.48-7.54 (m, 1H), 7.90 (d,J=7.84 Hz, 1H).

elemental analysis (C₁₂H₁₀N₂₀)

Calculated: C:72.71, H:5.08, N:14.13, 0:8.07.

Found: C:72.87, H:5.06, N:13.95.

Reference Example 4 [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile

2-Methylacetophenone (466 mmol, 62.5 g) and ethyl acetate (375 ml) wereadded in a four neck flask. While maintaining the internal temperatureat 25±5° C., a solution of bromine (489 mmol, 78.1 g) in ethyl acetate(180 ml) was slowly added dropwise. After the completion of the dropwiseaddition, the mixture was stirred at the same temperature for 1 hr. Tapwater (375 ml) was added dropwise at the internal temperature of notmore than 35° C., sodium sulfite (89.4 mmol, 11.3 g) was added, and themixture was stirred at room temperature for 1 hr. The organic layer wasseparated, and washed successively with 3% aqueous sodium hydrogencarbonate solution (375 ml) and 10% brine (375 ml) to give a solution of2-bromo-1-(2-methylphenyl)ethanone in ethyl acetate.

The solution of 2-bromo-1-(2-methylphenyl)ethanone in ethyl acetateobtained above was cooled, malononitrile (466 mmol, 30.8 g) was added atthe internal temperature of 5±5° C., and the dropping funnel was washedwith ethyl acetate (40 ml) and the washing was added.Diisopropylethylamine (513 mmol, 87.8 ml) was added dropwise at theinternal temperature of 10±5° C. After the dropwise addition, themixture was stirred at the internal temperature of 5±5° C. for 2 hr. Tapwater (375 ml) was added, and the mixture was partitioned at roomtemperature. The aqueous layer was further extracted with ethyl acetate(188 ml). The organic layers were combined, and washed with a mixture of1 N hydrochloric acid (18.8 ml) and 10% brine (188 ml), and 10% brine(188 ml) in this order. The organic layer was concentrated to about halfamount under reduced pressure. Methanol (375 ml) was added to theconcentrate, and the mixture was concentrated to about 388 g. Thisoperation was performed 3 times in total to give a slurry of the titlecompound and methanol.

Reference Example 5 [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile

2-Methylacetophenone (30 g, 223.5 mmol) and ethyl acetate (180 ml) weremixed, and a mixture of bromine (39 g) and ethyl acetate (90 ml) wasadded dropwise at room temperature over about 3 hr. Then, water (180 ml)was added dropwise, and the mixture was stirred at room temperature forabout 1 hr. Aqueous sodium sulfite solution (186 ml) was added dropwiseto the reaction mixture over about 1 hr, the mixture was partitioned,and the organic layer was washed with 3% aqueous sodium hydrogencarbonate solution (186 ml) and 10% aqueous sodium chloride solution(198 ml) to give a solution of 2-bromo-1-(2-methylphenyl)ethanone inethyl acetate.

Malononitrile (14.8 g) was added, and ethyl acetate (20 ml) was added.Diisopropylethylamine (42.1 ml) was added dropwise at about 10° C., andthe mixture was stirred for about 3 hr. Water (180 ml) was added, andthe organic layer was separated, and washed with a mixture of 1 Nhydrochloric acid (9 ml) and water (90 ml), and then with 10% aqueoussodium chloride solution (198 ml). The organic layer was concentratedunder reduced pressure, methanol (180 ml) was added, and the mixture wasconcentrated again under reduced pressure to about 187 g. Water (13 ml)was added at about 55° C., and the mixture was stirred at about 10° C.for about 1 hr. The precipitated crystals were collected by filtration,and washed with a mixture of methanol (23.1 ml) and water (3.5 ml). Thewet crystals were dried under reduced pressure to give the titlecompound (32.1 g, yield 72.5%).

Example 1 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

2-Chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (5.0 g, 22.7mmol), methanol (150 ml) and diisopropylethylamine (3.8 g, 29.5 mmol)were added in an autoclave, and the autoclave was purged with nitrogen.5% Palladium carbon (N.E. CHEMCAT, Standard, 0.5 g) was added. Then,under a hydrogen atmosphere (0.1 MPa), the mixture was vigorouslystirred at the internal temperature of 15-25° C. for about 4 hr. Afterpurging with nitrogen gas, the catalyst was filtered off, and washedwith methanol (15 ml). The organic layer was concentrated under reducedpressure to about 13 g. The amount of the content was adjusted to about28 g with ethanol. Water (40 ml) was added dropwise at the internaltemperature of 15-25° C., and the mixture was stirred at the sametemperature for 1 hr. The mixture was cooled to the internal temperatureof 0-10° C. and stirred for 1 hr. The precipitated crystals werecollected by filtration, washed with a cold mixed solution of ethanoland water (1:2, 15 ml) and dried under reduced pressure at 50° C. untila constant weight was reached to give the title compound (3.8 g, yield88%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.86 (d, J=1.67 Hz, 1H), 7.22-7.29 (m,3H), 7.71-7.74 (m, 2H), 12.18 (brs, 1H)

elemental analysis (C₁₁H₇N₂F)

Calculated: C:70.96, H:3.79, N:15.05, F:10.20.

Found: C:70.77, H:3.86, N:15.04.

melting point 158.5-160.5° C.

Example 2 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

2-Chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (25.0 g, 113mmol), ethanol (350 ml) and diisopropylethylamine (19.0 g, 147 mmol)were added in an autoclave, and the autoclave was purged with nitrogen.A suspension of 5% palladium carbon (N.E. CHEMCAT, Standard, 2.5 g) inethanol (25 ml) was added. Under a hydrogen atmosphere, the mixture wasvigorously stirred at the internal temperature of 15-25° C. for about 7hr. After purging with nitrogen gas, the catalyst was filtered off, andwashed with ethanol (75 ml). The filtrates were combined andconcentrated under reduced pressure to about 140 g. Water (200 ml) wasadded dropwise at the internal temperature of 20-30° C., and the mixturewas stirred at the same temperature for 0.5 hr. The mixture was cooledto the internal temperature of 0-10° C. and stirred for 1 hr. Theprecipitated crystals were collected by filtration, washed with a coldmixed solution of ethanol and water (1:2, 75 ml), and dried underreduced pressure at 50° C. until a constant weight was reached to givethe title compound (19.1 g, yield 90.7%).

¹H-NMR (500 MHz, CDCl₃) δ (ppm): 6.84-6.85 (m, 1H), 7.13-7.22 (m, 2H),7.25-7.29 (m, 1H), 7.38-7.39 (m, 1H), 7.56-7.60 (m, 1H), 9.36 (brs, 1H).

Example 3 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1H-pyrrole-3-carbonitrile (5.0 g, 26.9 mmol) and THF(33 ml) were added in a four neck flask, and the mixture was dissolvedat the internal temperature of 15-25° C. Acetic acid (55 ml) and water(11 ml) were added. After purging with nitrogen gas, Raney-nickel(Kawaken Fine Chemicals Co., Ltd., NDHT-90, 2.5 ml, wet weight 4 g) wasadded. Under a hydrogen atmosphere, the mixture was vigorously stirredat the internal temperature of 15-25° C. for about 3 hr. After purgingwith nitrogen gas, Raney-nickel was filtered off, and washed with ethylacetate (50 ml). 5 N Aqueous sodium hydroxide solution (about 180 ml)was added to the filtrate at the internal temperature of 10-35° C. toadjust the mixture to pH 7-8 and the mixture was partitioned. Theorganic layer was washed with 5% aqueous sodium hydrogen carbonatesolution (25 ml) and 5% brine (25 ml). Water (25 ml) was added to theorganic layer, and the mixture was adjusted with 6 N hydrochloric acidto pH 3.0-3.5 at the internal temperature of 15-25° C. After stirringovernight, the mixture was partitioned. The organic layer was washedwith 5% brine (25 ml), concentrated under reduced pressure to about 18g. After increasing the internal temperature to 65-70° C., the mixturewas cooled to the internal temperature of 45-55° C., and further stirredfor 1 hr. After cooling to the internal temperature of 15-25° C.,n-heptane (25 ml) was added dropwise, and the mixture was stirred at thesame temperature for 1 hr. Furthermore, the mixture was stirred at theinternal temperature of 0-10° C. for 1 hr. The precipitated crystalswere collected by filtration, washed with ethyl acetate:n-heptane (1:2,15 ml), and dried under reduced pressure at 50° C. until a constantweight was reached to give the title compound (23.9 g, yield 78%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.91 (d, J=1.6 Hz, 1H), 7.21-7.31 (m,3H), 7.75-7.80 (m, 2H), 9.76 (s, 1H), 12.17 (brs, 1H).

elemental analysis (C₁₁H₈NOF)

Calculated: C:69.83, H:4.26, N:7.40, 0:8.46, F:10.04.

Found: C:69.91, H:4.27, N:7.33.

melting point 123.0-126.0° C. dec.

Example 45-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde

5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (5.00 g, 26.43 mmol),N,N-dimethylpyridin-4-amine (0.65 g, 5.29 mmol), diisopropylethylamine(4.78 g, 37.00 mmol) and acetonitrile (18.5 ml) were added in a fourneck flask, and a solution of pyridine-3-sulfonyl chloride (5.63 g,31.71 mmol) in acetonitrile (5 ml) was added. Acetonitrile (1.5 ml) wasfurther added, and the mixture was stirred at the internal temperatureof 40-50° C. for 1.5 hr. The internal temperature was cooled to 30° C.,and water (15 ml) was added dropwise. The mixture was adjusted to pH 4-5with 0.5 N hydrochloric acid. Seed crystals (2.5 mg) of the titlecompound were added, and then water (about 30 ml) was added dropwise.After stirring at the internal temperature of 20-30° C. for 0.5 hr, theinternal temperature was cooled to 0-10° C., and the mixture was stirredfor 1 hr. The precipitated crystals were collected by filtration, washedwith a cold mixed solution of acetonitrile and water (1:2, 7.5 ml), andwater (7.5 ml×2), and dried under reduced pressure at 50° C. until aconstant weight was reached to give the title compound (7.57 g, yield86.7%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 6.68 (d, J=1.7 Hz, 1H), 7.01-7.05 (m,1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72(m, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.82 (dd,J=4.8, 1.5 Hz, 1H), 9.90 (s, 1H).

elemental analysis (C₁₆H₁₁N₂O₃SF)

Calculated: C: 58.17, H:3.36, N:8.48, 0:14.53, S:9.71, F: 5.75.

Found: C: 58.32, H:3.46, N:8.54, S:9.76, F:5.62.

melting point 106-108° C.

Example 51-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

To a nitrogen-purged flask were added N,N-dimethylacetamide (108 ml) andsodium borohydride (3.06 g, 81.74 mmol), and the mixture was dissolved(solution A). To another nitrogen-purged flask were added5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(60.00 g, 181.64 mmol) and methanol (300 ml), and then a solution (18.34g, 236.13 mmol) of 40% methylamine in methanol was added dropwise atroom temperature. The mixture was further stirred at the internaltemperature of 20-30° C. for 30 min. The internal temperature was cooledto −10° C., and solution A previously prepared was added dropwise at theinternal temperature of not more than 0° C. N,N-Dimethylacetamide (12ml) was added, and the mixture was stirred at the internal temperatureof −10 to 0° C. for 1 hr. 1 N HCl (360 ml) was added dropwise at theinternal temperature of not more than 20° C., and the mixture wasstirred at the internal temperature of 10-20° C. for 30 min. 12.5%Aqueous ammonia (240 ml), ethyl acetate (600 ml) and water (180 ml) wereadded, and the mixture was partitioned. Water (240 ml) and ethyl acetate(360 ml) were added to the aqueous layer and the mixture was extractedagain. The organic layers were combined and washed twice with 5% brine(360 ml). The organic layer was concentrated to about 253 g, andN,N-dimethylacetamide (480 ml) was added. The mixture was heated to theinternal temperature of 50° C., and fumaric acid (21.08 g, 181.64 mmol)was added. The mixture was stirred at the internal temperature of 50° C.for 30 min, cooled, and stirred at room temperature for 1 hr. Theprecipitated crystals were filtered, washed with a mixed solution ofethyl acetate and N,N-dimethylacetamide (1:2, 90 ml), and then ethylacetate (120 ml), and dried under reduced pressure at 50° C. to give acrude product (62.73 g).

The crude product (55.00 g) obtained above was suspended in a mixedsolution of methanol and water (7:3, 550 ml), and dissolved at theinternal temperature of 60-65° C. Activated carbon SHIRASAGI A(registered trade mark, 2.75 g) was added, and the mixture was stirredfor 10 min, filtered, and washed with a mixed solution of methanol andwater (7:3, 110 ml). The combined filtrate was heated to the internaltemperature of about 55° C., cooled to room temperature, and furtherstirred at the internal temperature of 0-10° C. for 1 hr. Theprecipitated crystals were filtered, washed with a mixed solution ofmethanol and water (1:1, 110 ml), and dried under reduced pressure at50° C. to give the title compound (47.50 g, yield 64.6%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.46 (s, 3H), 3.92 (s, 2H), 6.49 (s,2H), 6.51 (d, J=1.7 Hz, 1H), 7.08-7.13 (m, 1H), 7.20-7.26 (m, 2H),7.49-7.54 (m, 1H), 7.60-7.64 (m, 1H), 7.78 (s, 1H), 7.89 (dd, J=8.2, 1.6Hz, 1H), 8.57 (d, J=2.2 Hz, 1H), 8.89 (d, J=4.7 Hz, 1H), 10.81 (brs,2H), 1H not detected.

elemental analysis (C₂₁H₂₀N₃O₆SF)

Calculated: C:54.66, H:4.37, N:9.11, 0:20.80, S:6.95, F:4.12.

Found: C:54.68, H:4.31, N:9.07, S:7.00, F:4.15.

melting point 203-205° C.

Example 61-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate

N,N-Dimethylacetamide (18 ml) and sodium borohydride (0.52 g, 13.6 mmol)were added in a nitrogen-purged flask, and the mixture was dissolved(solution A). In another nitrogen-purged flask were added5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde(10.0 g, 30.3 mmol) and methanol (50 ml), and then a solution (3.06 g,39.4 mmol) of 40% methylamine in methanol was added dropwise at roomtemperature, and the mixture was further stirred at the internaltemperature of 20-30° C. for 30 min. The internal temperature waslowered to 5° C., and solution A previously prepared was added dropwiseat the internal temperature of 0-10° C. N,N-Dimethylacetamide (2 ml) wasadded, and the mixture was stirred at the internal temperature of 0-10°C. for 1 hr. 1 N HCl (70 ml) was added dropwise at the internaltemperature of not more than 20° C., and the mixture was stirred at theinternal temperature of 15-25° C. for 30 min. 12.5% Aqueous ammonia (60ml) and ethyl acetate (100 ml) were added to partition the mixture. 5%Brine (50 ml) and ethyl acetate (50 ml) were added to the aqueous layerand the mixture was extracted again. The organic layers were combinedand washed twice with 5% brine (60 ml). The organic layer wasconcentrated to about 25 ml, ethyl acetate (70 ml) was added, and themixture was concentrated again to about 38.0 ml. N,N-Dimethylacetamide(60 ml) was added, the mixture was heated to the internal temperature of45° C., and fumaric acid (3.51 g, 30.3 mmol) was added. After stirringat the internal temperature of 40-50° C. for 30 min, ethyl acetate (30ml) was added dropwise, and the mixture was stirred at the internaltemperature of 40-50° C. for 30 min. The mixture was cooled, and stirredat room temperature for 1 hr. The precipitated crystals were collectedby filtration, and washed with a mixed solution of ethyl acetate andN,N-dimethylacetamide (1:1, 15 ml), and then with ethyl acetate (30 ml)to give a crude product (wet product).

The crude product (wet product) obtained above was suspended in a mixedsolution of methanol and water (1:1, 100 ml), and dissolved at theinternal temperature of 60-70° C. Activated carbon SHIRASAGI A(registered trade mark, 0.30 g) was added, and the mixture was stirredfor 10 min, filtered, and washed with a mixed solution of methanol andwater (1:1, 20 ml). The combined filtrate was dissolved again at theinternal temperature of about 55-65° C., cooled to room temperature, andfurther stirred at the internal temperature of 0-10° C. for 1 hr. Theprecipitated crystals were collected by filtration, washed with a mixedsolution of methanol and water (1:1, 20 ml), and dried under reducedpressure at 50° C. to give the title compound (10.07 g, yield 72.1%).

¹H-NMR (500 MHz, DMSO-d₆) δ(ppm): 2.44 (s, 3H), 3.87 (s, 2H), 6.48-6.49(m, 3H), 7.09-7.12 (m, 1H), 7.20-7.25 (m, 2H), 7.50-7.55 (m, 1H),7.60-7.63 (m, 1H), 7.74-7.75 (m, 1H), 7.87-7.89 (m, 1H), 8.55-8.56 (m,1H), 8.87-8.89 (m, 1H), 3H not detected.

Example 7 (1)S-{3-cyano-5-(2-fluorophenyl)-1H-pyrrol-2-yl}benzenecarbothioate

To a solution of [2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile (30.1g, 149 mmol) in methanol (200 ml) were added thiobenzoic acid (28.2 ml,238 mmol) and triethylamine (2.08 ml, 14.9 mmol), and the mixture wasstirred at 60-70° C. for 2 hr. The mixture was allowed to cool, andmethanol (300 ml) and water (50 ml) were added at about 50° C. Afterstirring at room temperature for 1 hr and at 0-10° C. for 1 hr, thecrystals were collected by filtration, washed with an ice-cooled mixedsolution (120 ml) of water/methanol (4:1) and dried under reducedpressure at 50° C. to give the title compound (38.6 g, yield 80%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 12.9 (brs, 1H), 8.06-8.03 (m,2H), 7.82-7.77 (m, 2H), 7.69-7.64 (t, J=7.6 Hz, 2H), 7.41-7.32 (m, 3H),7.09 (s, 1H).

(2) 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

Under a nitrogen stream, a Raney-nickel catalyst (76 g),N,N-dimethylacetamide (206 ml) and morpholine (15.6 ml, 0.18 mol) wereplaced in a reactor, and the mixture was stirred at room temperature.While maintaining the internal temperature at not more than 40° C., asolution of S-{3-cyano-5-(2-fluorophenyl)-1H-pyrrol-2-yl}benzenecarbothioate (38.6 g, 0.12 mol) in N,N-dimethylacetamide (180 ml)was slowly added dropwise. The mixture was heated under reflux at theinternal temperature of 100-110° C. for 1 hr. After allowing the mixtureto cool to room temperature, the Raney-nickel catalyst was filtered off,and washed with ethyl acetate (120 ml). Ethyl acetate (280 ml) and 10%brine (600 ml) were added to the filtrate, and the mixture was extractedand partitioned. The aqueous layer was extracted 3 times with ethylacetate (200 ml, 100 ml, 100 ml), the organic layers were combined, andwashed with water (1 L). Ethanol (120 ml) was added to the concentrate,water (240 ml) was added while stirring with heating at 60-65° C., andthe mixture was further stirred at the same temperature for 1 hr. Themixture was allowed to cool to 30° C. or below, and stirred at 0-10° C.for 1 hr. The crystals were collected by filtration, and washed with anice-cooled mixed solution (40 ml) of water/ethanol (1:2), and driedunder reduced pressure at 50° C. until a constant weight was reached togive the title compound (17.6 g, yield 79%).

¹H-NMR (DMSO-d₆, TMS, 300 MHz) δ(ppm): 9.3 (br, 1H), 7.6-7.5 (m, 1H),7.4-7.3 (m, 1H), 7.3-7.1 (m, 3H), 6.84 (d, J=1.7 Hz, 1H).

Example 8 (1)2,2′-disulfanediylbis[5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile]

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (5.05 g, 25 mmol),methanol (50.5 ml), thioacetic acid (1.79 ml, 25 mmol) and triethylamine(0.7 ml, 5 mmol) were charged in a 100 ml four neck flask, and themixture was heated under reflux for 10 hr. Water (10.2 ml) was added,and the mixture was refluxed for 1 hr. The mixture was allowed to cooland ice-cooled, and the precipitated crystals were collected byfiltration and washed by sprinkling an ice-cooled mixed solution (20.2ml) of water/methanol (1:10), and dried under reduced pressure at 50° C.to give the title compound (4.64 g, yield 85%).

(2) 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

Under a nitrogen stream, Raney-nickel (12.6 g), N,N-dimetylacetamide (30ml), morpholine (1.36 ml, 15.6 mmol) and a solution of2,2′-dithiobis[5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile] (4.50 g,10.4 mmol) in N,N-dimethylacetamide (15 ml) were charged in a 100 mlfour neck flask, and the mixture was heated under reflux at 105° C. for5.5 hr. The reaction mixture was cooled, and the catalyst was filteredoff, and washed with N,N-dimethylacetamide and ethyl acetate in thisorder. 5% Brine was added to the filtrate and washings, the mixture waspartitioned, and the aqueous layer was extracted 3 times with ethylacetate. The organic layers were combined, washed with 5% brine, andconcentrated to dryness under reduced pressure. Ethanol (22.5 ml) wasadded to the residue, and the mixture was dissolved by heating. Water(45 ml) was added to cause crystallization. The slurry was heated underreflux for 1 hr, and allowed to cool and ice-cooled, and the crystalswere collected by filtration. The crystals were washed by sprinkling anice-cooled mixed solution (10 ml) of water/ethanol (1:2) and dried underreduced pressure at 50° C. to give the title compound (3.45 g, yield85%).

¹H-NMR (DMSO-d₆, TMS, 300 MHz) δ(ppm): 9.3 (br, 1H), 7.6-7.5 (m, 1H),7.4-7.3 (m, 1H), 7.3-7.1 (m, 3H), 6.84 (d, J=1.7 Hz, 1H).

mass spectrometry (EI, m/z) (rel intensity): 186 (M+, 100), 158 (20),132 (11).

elemental analysis (C₁₁H₇N₂F)

Calculated: C, 70.96; H, 3.79; N, 15.05.

Found: C, 70.69; H, 3.89; N, 14.86.

Example 9 2-(methylsulfanyl)-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (2.0 g, 10.9 mmol), acetic acid(3.26 g, 54.3 mmol) and methanol (20 ml) were charged in a reactor, 15%aqueous sodium thiomethoxide solution (7.6 g) was added dropwise, andthe mixture was heated under reflux for 6 hr. The reaction mixture wascooled to room temperature, and stirred at room temperature for 1 hr andat 0-10° C. for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (2 ml) of water/methanol (1:1) anddried under reduced pressure at 50° C. to give the title compound (2.1g, yield 90%).

¹H-NMR (300 MHz, TMS, DMSO-d6) δ(ppm): 12.5 (brs, 1H), 7.72-7.69 (m,2H), 7.43-7.38 (m, 2H), 7.30-7.28 (m, 1H), 6.98 (s, 1H), 2.52 (s, 3H).

Example 105-(2-methylphenyl)-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile

[2-(2-Methylphenyl)-2-oxoethyl]propanedinitrile (2.0 g, 10.9 mmol),acetic acid (3.26 g, 54.3 mmol) and methanol (20 ml) were charged in areactor, 15% aqueous sodium thiomethoxide solution (7.6 g) was addeddropwise, and the mixture was heated under reflux for 6 hr. The reactionmixture was cooled to room temperature, and stirred at room temperaturefor 1 hr and at 0-10° C. for 1 hr. The crystals were collected byfiltration, and washed with an ice-cooled mixed solution (2 ml) ofwater/methanol (1:1). The crystals were dried under reduced pressure at50° C. to give the title compound (1.8 g, yield 78%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 8.5-8.7 (brs, 1H), 7.2-7.3 (m, 4H),6.51 (d, J=2.8 Hz, 1H), 2.50 (s, 3H), 2.4 (s, 3H).

mass spectrometry (EI, m/z) 228[M+].

elemental analysis (C₁₃H₁₂N₂S)

Calculated: C, 68.39; H, 5.30; N, 12.27; S, 14.04.

Found: C, 68.30; H, 5.26; N, 12.30; S, 14.11.

melting point 148-149° C.

Example 11 5-tert-butyl-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile

[2-(tert-Butyl)-2-oxoethyl]propanedinitrile (1.0 g, 6.1 mmol), aceticacid (1.1 g, 18.3 mmol) and methanol (10 ml) were charged in a reactor,15% aqueous sodium thiomethoxide solution (5.7 ml, 12.2 mmol) was addeddropwise, and the mixture was heated under reflux for 1 hr. Water andethyl acetate were added to the reaction mixture, the mixture waspartitioned, and the organic layer was washed with saturated aqueoussodium hydrogen carbonate. The organic layer was concentrated, a mixtureof methanol and water was added to the concentrated residue, and themixture was stirred at room temperature for 1 hr. The crystals werecollected by filtration, washed with an ice-cooled mixed solution (1 ml)of water/methanol (1:1), and dried under reduced pressure at 50° C. togive the title compound (1.1 g, yield 84%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 8.3 (brs, 1H), 6.18 (d, J=2.9 Hz,1H), 2.47 (s, 3H), 1.29 (s, 9H).

high resolution mass spectrometry (EI, m/z) (C₁₀H₁₄N₂S)

Calculated 194.0878

Found 194.0877

Example 125-(3-methoxyphenyl)-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile

[2-(3-Methoxyphenyl)-2-oxoethyl]propanedinitrile (1.0 g, 4.67 mmol),acetic acid (0.84 g, 14.0 mmol) and methanol (10 ml) were charged in areactor, 15% aqueous sodium thiomethoxide solution (4.35 ml, 9.33 mmol)was added dropwise, and the mixture was heated under reflux for 6 hr.The reaction mixture was cooled to room temperature, water (5 ml) wasadded, and the mixture was stirred at room temperature for 1 hr and at0-10° C. for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (2 ml) of water/methanol (1:1), anddried under reduced pressure at 50° C. to give the title compound (0.74g, yield 70%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 8.90 (brs, 1H), 7.32 (t, J=8.0 Hz,1H), 7.03 (d, J=7.7 Hz, 1H), 6.96-6.97 (m, 1H), 6.86 (dd, J=5.4 and 2.4Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 3.83 (s, 3H), 2.52 (s, 3H).

high resolution mass spectrometry (EI, m/z) (C₁₃H₁₂N₂OS)

Calculated 244.0670

Found 244.0664

melting point 112-113° C.

Example 135-(4-bromophenyl)-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile

[2-(4-Bromophenyl)-2-oxoethyl]propanedinitrile (1.5 g, 5.70 mmol),acetic acid (1.7 g, 28.5 mmol) and methanol (15 ml) were charged in areactor, 15% aqueous sodium thiomethoxide solution (10.7 ml, 22.8 mmol)was added dropwise, and the mixture was heated under reflux for 5 hr.The reaction mixture was cooled to room temperature, and the mixture wasstirred at room temperature for 1 hr and at 0-10° C. for 1 hr. Thecrystals were collected by filtration, washed with an ice-cooled mixedsolution (2 ml) of water/methanol (1:1), and dried under reducedpressure at 50° C. to give the title compound (1.14 g, yield 68%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 8.7 (brs, 1H), 7.54 (d, J=8.6 Hz,2H), 7.30 (d, J=6.7 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 2.54 (s, 3H).

high resolution mass spectrometry (EI, m/z) (C₁₂H₉BrN₂S)

Calculated 291.9670

Found 291.9684

Example 142-(methylsulfanyl)-5-naphthalen-2-yl-1H-pyrrole-3-carbonitrile

(2-Naphthalen-2-yl-2-oxoethyl)propanedinitrile (1.0 g, 4.25 mmol),acetic acid (1.27 g, 21.3 mmol) and methanol (20 ml) were charged in areactor, 15% aqueous sodium thiomethoxide solution (9.8 ml, 21.3 mmol)was added dropwise, and the mixture was heated under reflux for 5 hr.The reaction mixture was cooled to room temperature, and stirred at roomtemperature for 1 hr and at 0-10° C. for 1 hr. The crystals werecollected by filtration, washed with an ice-cooled mixed solution (2 ml)of water/methanol (1:1), and dried under reduced pressure at 50° C. togive the title compound (0.97 g, yield 86%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 8.86 (brs, 1H), 7.83-7.90 (m, 4H),7.47-7.59 (m, 3H), 6.82 (d, J=2.7 Hz, 1H), 2.56 (s, 3H).

high resolution mass spectrometry (EI, m/z) (C₁₆H₁₂N₂S)

Calculated 264.0721

Found 264.0715

Example 15 (1)5-(4-fluorophenyl)-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile

[2-(4-Fluorophenyl)-2-oxoethyl]propanedinitrile (4.0 g, 19.8 mmol),acetic acid (6.0 g, 99.0 mmol) and methanol (40 ml) were charged in areactor, 15% aqueous sodium thiomethoxide solution (14.0 ml, 29.7 mmol)was added dropwise, and the mixture was heated under reflux for 6 hr.The reaction mixture was cooled to room temperature, and stirred at roomtemperature for 1 hr and at 0-10° C. for 1 hr. The crystals werecollected by filtration, washed with an ice-cooled mixed solution (2 ml)of water/methanol (1:1), and dried under reduced pressure at 50° C. togive the title compound (3.6 g, yield 78%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 12.5 (brs, 1H), 7.77-7.72 (m,2H), 7.26 (t, J=8.9 Hz, 2H), 6.96 (s, 1H), 2.51 (s, 3H).

elemental analysis (C12H₉FN₂S)

Calculated: C, 62.05; H, 3.91; N, 12.06; S, 13.80; F, 8.18.

Found: C, 61.90; H, 3.75; N, 12.30; S, 13.79; F, 8.17.

melting point 187-188° C.

(2) 5-(4-fluorophenyl)-2-(methylsulfonyl)-1H-pyrrole-3-carbonitrile

Under ice-cooling, to a solution of5-(4-fluorophenyl)-2-(methylsulfanyl)-1H-pyrrole-3-carbonitrile (2 g,8.61 mmol) in ethyl acetate (20 ml) was added m-chloroperbenzoic acid(3.26 g, 19 mmol), and the mixture was stirred at room temperature for 4hr. The reaction mixture was washed successively with aqueous sodiumsulfite solution, saturated aqueous sodium hydrogen carbonate and water.The organic layer was concentrated to give the title compound (2.0 g,yield 88%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 7.90-7.85 (m, 2H), 7.32 (t, J=8.9Hz, 2H), 7.23 (s, 1H), 3.34 (s, 3H).

Example 162-[(2,4-dichlorophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), triethylamine(0.08 ml, 0.543 mmol), methanol (10 ml) and 2,4-dichlorobenzenethiol(1.46 g, 8.15 mmol) were charged in a reactor, and the mixture wasstirred at 40° C. for 4 hr. The mixture was allowed to cool and stirredat room temperature for 1 hr. The crystals were collected by filtration,and washed with an ice-cooled mixed solution (1 ml) of water/methanol(1:1). The crystals were dried under reduced pressure at 50° C. to givethe title compound (1.46 g, yield 78%) 1H-NMR (300 MHz, TMS, CDCl₃)δ(ppm): 9.0 (brs, 1H), 7.48-7.42 (m, 6H), 7.15-7.14 (m, 1H), 6.92 (d,J=8.5 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H).

mass spectrometry (EI, m/z) 344 [M+].

high resolution mass spectrometry (C₁₇H₁₀C₁₂N₂S)

Calculated 343.9942

Found 343.9944

melting point 169.0-170.0° C.

Example 172-(naphthalen-2-ylsulfanyl)-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), triethylamine(0.08 ml, 0.543 mmol), methanol (10 ml) and 2-naphthalenethiol (1.3 g,8.15 mmol) were charged in a reactor, and the mixture was stirred at 40°C. for 0.5 hr. Water (2 ml) was added, and the mixture was stirred atroom temperature for 1 hr. The crystals were collected by filtration,washed with an ice-cooled mixed solution (1 ml) of water/methanol (1:1),and dried under reduced pressure at 50° C. to give the title compound(0.63 g, yield 35%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 9.0 (brs, 1H), 7.8-7.3 (m, 12H),6.80 (d, J=2.8 Hz, 1H).

high resolution mass spectrometry (EI, m/z) (C₂₁H₁₄N₂S)

Calculated 326.0878

Found 326.0883

melting point 93.0-94.4° C.

Example 182-[(2-aminophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (5.0 g, 27.1 mmol), triethylamine(0.4 ml, 2.71 mmol), methanol (50 ml) and o-aminobenzenethiol (5.0 ml,40.7 mmol) were charged in a reactor, and the mixture was stirred at 40°C. for 1 hr. The reaction mixture was concentrated, and the concentratewas purified by silica gel column chromatography to give the titlecompound (2.3 g, yield 29%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 9.60 (brs, 1H), 7.56-7.53 (m, 1H),7.37-7.35 (m, 4H), 7.27-7.20 (m, 2H), 6.85-6.60 (m, 2H), 6.60 (d, J=2.9Hz, 1H), 4.5-3.50 (br, 2H).

high resolution mass spectrometry (EI, m/z) (C₁₇H₁₃N₃S)

Calculated 291.0830

Found 291.0826

melting point 159.0-160.0° C.

Example 192-[(2-bromophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (5.0 g, 27.1 mmol), triethylamine(0.4 ml, 2.71 mmol), methanol (50 ml) and o-bromobenzenethiol (5.0 ml,40.7 mmol) were charged in a reactor, and the mixture was stirred at 40°C. for 1 hr. The mixture was allowed to cool, and stirred at roomtemperature for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (5 ml) of water/methanol (1:1), anddried under reduced pressure at 50° C. to give the title compound (6.9g, yield 72%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 9.2 (brs, 1H), 7.55-7.40 (m, 6H),7.19-7.06 (m, 2H), 6.90-6.86 (m, 1H), 6.81 (d, J=2.8 Hz, 1H).

mass spectrometry (EI, m/z) 354[M⁺]

high resolution mass spectrometry (C₁₇H₁₁BrN₂S)

Calculated 353.9826

Found 353.9816

melting point 126.0-127.0° C.

Example 202-[(3-bromophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), triethylamine(0.08 ml, 0.543 mmol), methanol (10 ml) and m-bromobenzenethiol (1.46 g,8.15 mmol) were charged in a reactor, and the mixture was stirred at 40°C. for 4 hr. The mixture was allowed to cool, and stirred at roomtemperature for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (1 ml) of water/methanol (1:1), anddried under reduced pressure at 50° C. to give the title compound (1.6g, yield 80%).

¹H-NMR (300 MHz, TMS, CDCl₃) δ(ppm): 9.0 (brs, 1H), 7.49-7.42 (m, 4H),7.35-7.33 (m, 3H), 7.15-7.14 (m, 2H), 6.80 (d, J=2.8 Hz, 1H).

mass spectrometry (EI, m/z) 354 [M+]

high resolution mass spectrometry (C₁₇H₁₁BrN₂S)

Calculated 353.9826

Found 353.9824

melting point 141.0-142.0° C.

Example 21 5-phenyl-2-(pyridin-4-ylsulfanyl)-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), methanol (10ml) and 4-mercaptopyridine (1.2 g, 8.15 mmol) were charged in a reactor,and the mixture was heated under reflux for 7 hr. The mixture wasallowed to cool and stirred at room temperature for 1 hr. The crystalswere collected by filtration, washed with an ice-cooled mixed solution(1 ml) of water/methanol (1:1), and dried under reduced pressure at 50°C. to give the title compound (1.2 g, yield 80%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 13.0 (brs, 1H), 8.43 (d, J=6.2Hz, 2H), 7.78 (d, J=7.2 Hz, 2H), 7.47-7.29 (m, 4H), 7.05 (d, J=6.5 Hz,2H).

high resolution mass spectrometry (EI, m/z) (C₁₆H₁₁N₃S)

Calculated 277.0674

Found 277.0678

melting point 172-174° C.

Example 222-[(4-aminophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), methanol (10ml) and p-aminobenzenethiol (1.26 g, 8.15 mmol) were charged in areactor, and the mixture was heated under reflux for 4 hr. The mixturewas allowed to cool, water (5 ml) was added, and the mixture was stirredat room temperature for 1 hr. The crystals were collected by filtration,washed with an ice-cooled mixed solution (1 ml) of water/methanol (1:1),and dried under reduced pressure at 50° C. to give the title compound(1.05 g, yield 66%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 7.76 (d, J=7.2 Hz, 2H), 7.44 (t,J=7.5 Hz, 2H), 7.32 (t, J=7.4 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.06 (s,1H), 6.57 (d, J=8.6 Hz, 2H), 5.40 (s, 2H).

elemental analysis (C₁₇H₁₃N₃S)

Calculated: C, 70.08; H, 4.50; N, 14.42; S, 11.00.

Found: C, 69.93; H, 4.43; N, 14.49; S, 11.05.

melting point 146-147° C.

Example 232-[(2-fluorophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), triethylamine(0.08 ml, 0.543 mmol), methanol (10 ml) and 2-fluorobenzenethiol (1.04g, 8.15 mmol) were charged in a reactor, and the mixture was stirred at40° C. for 4 hr. The mixture was allowed to cool, and stirred at roomtemperature for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (1 ml) of water/methanol (1:1), anddried under reduced pressure at 50° C. to give the title compound (1.1g, yield 69%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 12.9 (brs, 1H), 7.77 (d, J=7.2Hz, 2H), 7.43 (t, J=7.1 Hz, 2H), 7.34-7.29 (m, 3H), 7.21-7.17 (m, 2H),6.93 (t, J=7.7 Hz, 1H).

mass spectrometry (EI, m/z) 294[M+].

high resolution mass spectrometry (C₁₇H₁₁FN₂S)

Calculated 294.0627

Found 294.0620

melting point 152-153° C.

Example 242-[(4-nitrophenyl)sulfanyl]-5-phenyl-1H-pyrrole-3-carbonitrile

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 5.43 mmol), triethylamine(0.08 ml, 0.543 mmol), methanol (10 ml) and 4-nitrobenzenethiol (1.46 g,8.15 mmol) were charged in a reactor, and the mixture was stirred at 40°C. for 4 hr. The mixture was allowed to cool and stirred at roomtemperature for 1 hr. The crystals were collected by filtration, washedwith an ice-cooled mixed solution (1 ml) of water/methanol (1:1), anddried under reduced pressure at 50° C. to give the title compound (1.7g, yield 80%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 13.1 (brs, 1H), 8.20 (d, J=9.0Hz, 2H), 7.78 (d, J=7.2 Hz, 2H), 7.45 (t, J=6.5 Hz, 2H), 7.33-7.30 (m,4H).

high resolution mass spectrometry (EI, m/z) (C₁₇H₁₁N₃O₂S)

Calculated 321.0572

Found 321.0566

melting point 230-231° C.

Example 25 [(3-cyano-5-phenyl-1H-pyrrol-2-yl)sulfanyl]acetic acid

(2-Phenyl-2-oxoethyl)propanedinitrile (1.0 g, 54.3 mmol), methanol (150ml) and thioglycolic acid (6.0 g, 52.6 mmol) were charged in a reactor,and the mixture was heated under reflux for 0.5 hr. The mixture wasallowed to cool and stirred at room temperature for 0.5 hr and underice-cooling for 0.5 hr. The crystals were collected by filtration. Thewet crystals were washed with ethyl acetate (60 ml), and dried underreduced pressure at 50° C. to give the title compound (8.8 g, yield60%).

¹H-NMR (300 MHz, TMS, DMSO-d₆) δ(ppm): 7.60 (d, J=8.0 Hz, 2H), 7.39 (t,J=7.6 Hz, 2H), 7.26-7.21 (m, 1H), 6.66 (s, 1H), 2.51 (s, 2H).

high resolution mass spectrometry (FAB) (C₁₃H₁₀N₂O₂S)

Calculated 257.0835 [M-H]⁻

Found 257.0390 [M-H]⁻

Example 26 4-(2-fluorophenyl)-2-(iminomethyl)-4-oxobutanenitrile

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (3.00 g, 14.8 mmol) andTHF (30 ml) were weighed, placed in a 50 ml flask and dissolved. Themixture was purged with an inert gas, 5% Pd—C (1.20 g, corresponding to2 mol % based on Pd) was added, and washed with THF (5 ml). Then, themixture was purged with hydrogen, and reacted at room temperature for 4hr (catalytic reduction was performed until the starting material wasless than 2%). The catalyst was filtered off, and washed with THF (15ml), and concentrated to dryness under reduced pressure to give a crudeproduct (3.32 g) of the title compound. Therefrom 2.44 g was suspendedin ethyl acetate (5 ml)/n-hexane (5 ml), and the suspension was stirredfor 0.5 hr. The suspension was suction filtered, washed with ethylacetate (2 ml)/n-hexane (2 ml), and dried under reduced pressure at 50°C. to give the title compound (1.47 g, yield 65.9%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 3.66 (d, J=2.3 Hz, 2H), 6.37 (m, 2H),6.79 (t, J=11.1 Hz, 1H), 7.28-7.35 (m, 2H), 7.62-7.64 (m, 1H), 7.77-7.83(m, 1H).

elemental analysis (C₁₁H₉N₂OF)

Calculated: C:64.70, H:4.44, N:13.72, 0:7.84, F:9.30.

Found: C:64.78, H:4.43, N:13.66.

melting point 119.5-122.5° C.

Example 27 4-naphthalen-2-yl-2-(iminomethyl)-4-oxobutanenitrile

The reaction was performed by an operation similar to that in Example 26and using (2-naphthalen-2-yl-2-oxoethyl)propanedinitrile (700 mg), andconcentrated under reduced pressure. Ethyl acetate (10 ml) was added tothe concentrate, and the mixture was stirred for 15 min. The crystalswere collected by suction filtration, washed with ethyl acetate (2 ml),and dried under reduced pressure at 50° C. for 2 hr to give the titlecompound (617 mg, yield 61.2%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 3.91 (s, 14/10H), 3.98 (s, 6/10H),6.40 (brd, J=11.0 Hz, 14/10H), 6.55 (brd, J=11.2 Hz, 6/10H), 6.91 (t,J=11.0 Hz, 7/10H), 7.03 (t, J=11.2 Hz, 3/10H), 7.57-7.67 (m, 20/10H),7.91-8.00 (m, 30/10H), 8.09 (d, J=7.5 Hz, 10/10H), 8.68 (brs, 10/10H).

elemental analysis (C₁₅H₁₂N₂O)

Calculated: C:76.25, H:5.12, N:11.86, 0:6.77.

Found: C:76.13, H:5.19, N:11.77.

melting point 154.0-157.0° C.

Example 28 4-(4-methoxyphenyl)-2-(iminomethyl)-4-oxobutanenitrile

The reaction was performed by an operation similar to that in Example 26and using [2-(4-methoxyphenyl)-2-oxoethyl]propanedinitrile (5.00 g) togive the title compound (6.14 g). Ethyl acetate (3 ml) was added to 0.95g thereof, and the mixture was stirred at room temperature for 0.5 hr.The crystals were collected by suction filtration, washed with ethylacetate (2 ml), and dried under reduced pressure at 50° C. for 2 hr togive a further purified title compound (0.24 g). 1H-NMR (300 MHz,DMSO-d₆) δ(ppm): 3.67 (s, 12/7H), 3.73 (s, 2/7H), 3.82 (s, 21/7H), 6.36(brd, J=11.0 Hz, 12/7H), 6.45 (brd, J=11.0 Hz, 2/7H), 6.80 (t, J=11.0Hz, 6/7H), 6.94 (t, J=11.0 Hz, 1/7H), 7.00-7.05 (m, 14/7H), 7.93 (d,J=8.9 Hz, 14/7H).

elemental analysis (C₁₂H₁₂N₂O₂)

Calculated: C:66.65, H:5.59, N:12.96, 0:14.79.

Found: C:66.61, H:5.44, N:13.09.

melting point 133.5-134.5° C.

Example 29 4-(4-methylphenyl)-2-(iminomethyl)-4-oxobutanenitrile

The reaction was performed by an operation similar to that in Example 26and using [2-(4-methylphenyl)-2-oxoethyl]propanedinitrile (980 mg) togive the title compound (867 mg, yield 87.6%). Ethyl acetate (4 ml) wasadded thereto, and the mixture was stirred at room temperature for 1 hr.The crystals were collected by suction filtration, washed with ethylacetate (2 ml), and dried under reduced pressure at room temperature for2 hr to give a further purified title compound (345 mg).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.35 (s, 12/4H), 3.70 (s, 6/4H), 3.76(s, 2/4H), 6.31 (brd, J=11.1 Hz, 6/4H), 6.45 (brd, J=11.1 Hz, 2/4H),6.81 (t, J=11.1 Hz, 3/4H), 6.94 (t, J=11.1 Hz, 1/4H), 7.30 (d, J=8.1 Hz,8/4H), 7.85 (d, J=8.1 Hz, 8/4H).

elemental analysis (C₁₂H₁₂N₂O)

Calculated: C:71.98, H:6.04, N:13.99, 0:7.99.

Found: C:71.94, H:6.08, N:13.95.

melting point 158.0-160.0° C.

Example 30 4-(2-methylphenyl)-2-(iminomethyl)-4-oxobutanenitrile

The reaction was performed by an operation similar to that in Example 26and using [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile (1.00 g). TheTHF solution was concentrated to dryness under reduced pressure. Ethylacetate (2 ml) was added thereto, and the mixture was stirred at roomtemperature for 0.5 hr. The crystals were collected by suctionfiltration, washed with ethyl acetate (1 ml), and dried under reducedpressure at 50° C. for 2 hr to give a further purified title compound(498 mg, yield 49.3%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.39 (s, 15/6H), 2.41 (s, 3/6H), 3.66(s, 10/6H), 3.73 (s, 2/6H), 6.37 (brd, J=11.0 Hz, 10/6H), 6.50 (brd,J=11.0 Hz, 2/6H), 6.82 (t, J=11.0 Hz, 5/6H), 6.96 (t, J=11.0 Hz, 1/6H),7.27-7.34 (m, 12/6H), 7.39-7.44 (m, 6/6H), 7.75 (d, J=7.7 Hz, 5/6H),7.82 (d, J=7.8 Hz, 1/6H).

elemental analysis (C₁₂H₁₂N₂O)

Calculated: C:71.98, H:6.04, N:13.99, 0:7.99.

Found: C:72.06, H:6.05, N:14.00.

melting point 111.0-114.0° C.

Example 31 2-(iminomethyl)-4-oxo-4-phenylbutanenitrile

The reaction was performed by an operation similar to that in Example 29and using (2-oxo-2-phenylethyl)propanedinitrile (1.82 g) to give thetitle compound (804 mg, yield 43.7%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 3.75 (s, 10/8H), 3.81 (s, 6/8), 6.34(brd, J=11.0 Hz, 10/8H), 6.47 (d, J=11.0 Hz, 6/8H), 6.82 (t, J=11.0 Hz,5/8H), 6.96 (t, J=11.0 Hz, 3/8H), 7.48-7.56 (m, 16/8H), 7.59-7.65 (m,8/8H), 7.94-7.98 (m, 16/8H).

elemental analysis (C₁₁H₁₀N₂O)

Calculated: C:70.95, H:5.41, N:15.04, 0:8.59.

Found: C:70.97, H:5.34, N:15.14.

melting point 89.0-90.0° C.

Example 32 5-(4-methylphenyl)-1H-pyrrole-3-carbonitrile

To 4-(4-methylphenyl)-2-(iminomethyl)-4-oxobutanenitrile (217 mg) wereadded THF (1 ml) and acetic acid (0.44 ml), and the mixture was reactedat the outer temperature of 50° C. The reaction mixture was extractedwith ethyl acetate, and washed successively with aqueous sodium hydrogencarbonate solution and water. Ethyl acetate was concentrated underreduced pressure. The residue was crystallized from ethyl acetate (1ml)/n-hexane (7 ml). The crystals were collected by suction filtration,washed with ethyl acetate (0.2 ml)/n-hexane (1.6 ml), and dried underreduced pressure at 45° C. for 3 hr to give the title compound (110 mg,yield 55.7%). 1H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.27 (s, 3H), 6.84 (dd,J=1.6, 2.9 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.65(dd, J=1.6, 2.3 Hz, 1H), 12.13 (brs, 1H).

elemental analysis (C₁₂H₁₀N₂)

Calculated: C:79.10, H:5.53, N:15.37.

Found: C:79.00, H:5.47, N:15.50.

melting point 169.0-171.0° C.

Example 33 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (10.0 g, 49.46 mmol) andTHF (95 ml) were weighed, placed in a 200 ml flask and dissolved. Themixture was purged with an inert gas, 5% Pd—C (4.0 g, corresponding to 2mol % based on Pd) was added, and washed with THF (5 ml). Then, themixture was purged with hydrogen and reacted at room temperature.Catalytic reduction was performed until the starting material becameless than 2%. The catalyst was filtered off, and washed twice with THF(20 ml). The THF solution was concentrated under reduced pressure toabout 28 g. Acetic acid (20 ml) was added thereto, and the mixture wasreacted at the outer temperature of 50° C. for 4 hr. Water (100 ml) wasadded dropwise to this reaction mixture. The crystals were aged at roomtemperature, collected by suction filtration, washed with cold aqueousethanol solution (ethanol:water=1:4, 20 ml), and dried under reducedpressure at 50° C. to give 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile(7.38 g).

7.00 g of the obtained 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile wassuspended in acetic acid (14 ml), and the suspension was stirred at roomtemperature for 1 hr. The solid was collected by suction filtration,washed with cold aqueous ethanol solution (ethanol:water=1:4, 10 ml),and dried under reduced pressure at 50° C. to give5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (5.96 g, yield 68.2%).

Example 34 5-naphthalen-2-yl-1H-pyrrole-3-carbonitrile

(2-Naphthalen-2-yl-2-oxoethyl)propanedinitrile (2.00 g) was dissolved inTHE (50 ml). The mixture was purged with an inert gas, 5% Pd—C (1.2 g)was added, and the mixture was purged with an inert gas. Then, themixture was purged with hydrogen, and reacted at room temperature for4.5 hr. Catalytic reduction was performed until the starting materialbecame less than 2%. The catalyst was filtered off and washed with THF.The filtrate was concentrated under reduced pressure. Acetic acid (30ml) was added thereto, and the mixture was reacted at the outertemperature of 50° C. for 4 hr. Ethyl acetate was added, and the mixturewas partitioned. The organic layer was washed with water, saturatedaqueous sodium hydrogen carbonate and saturated brine in this order. Theorganic layer was concentrated under reduced pressure to give a residue(1.66 g). This was quantified by HPLC to give the title compound (1.20g, yield 65.8%). This was purified by column chromatography (ethylacetate/n-hexane) to give the title compound (858 mg, yield 46.1%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 7.08 (s, 1H), 7.42-7.52 (m, 2H),7.76-7.93 (m, 5H), 8.20 (s, 1H), 12.40 (brs, 1H).

melting point 200.5-206.5° C.

Example 35 5-(2,4-dimethoxyphenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(2,4-dimethoxyphenyl)-2-oxoethyl]propanedinitrile (700 mg).Quantification by HPLC gave the title compound (493 mg, yield 75.4%).Purification by column chromatography (ethyl acetate/n-hexane) gave thetitle compound (410 mg, yield 62.7%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 3.77 (s, 3H), 3.85 (s, 3H), 6.57 (d,J=8.5 Hz, 1H), 6.62 (s, 1H), 6.75 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.56(s, 1H), 11.68 (brs, 1H).

elemental analysis (C₁₃H₁₂N₂O₂)

Calculated: C:68.41, H:5.30, N:12.27, 0:14.02.

Found: C:68.44, H:5.31, N:12.43.

melting point 129.0-130.0° C.

Example 36 5-(4-methoxyphenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(4-methoxyphenyl)-2-oxoethyl]propanedinitrile (5.0 g).Quantification by HPLC gave the title compound (3.4 g, yield 87.3%).This was recrystallized from ethyl acetate/n-hexane (1:2) to give thetitle compound (3.1 g, yield 80.4%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 3.75 (s, 3H), 6.77 (s, 1H), 6.95 (d,J=8.7 Hz, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.62 (d, J=0.6 Hz, 1H), 12.07(brs, 1H).

elemental analysis (C₁₂H₁₀N₂O)

Calculated: C:72.71, H:5.08, N:14.13, 0:8.07.

Found: C:72.48, H:5.06, N:14.11.

melting point 185.0-186.0° C.

Example 37 5-(4-methylphenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(4-methylphenyl)-2-oxoethyl]propanedinitrile (5.0 g).Quantification by HPLC gave the title compound (3.4 g, yield 73.8%).

Example 38 5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile (1.00 g) togive the title compound (535 mg, yield 63.1%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.37 (s, 3H), 6.63 (d, J=1.4 Hz, 1H),7.23-7.31 (m, 3H), 7.38-7.41 (m, 1H), 7.71 (d, J=1.4 Hz, 1H), 11.98(brs, 1H).

elemental analysis (C₁₂H₁₀N₂)

Calculated: C:79.10, H:5.53, N:15.37.

Found: C:78.94, H:5.55, N:15.26.

melting point 151.0-152.5° C.

Example 39 5-phenyl-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using (2-oxo-2-phenylethyl)propanedinitrile (4.5 g). Quantificationby HPLC gave the title compound (2.4 g, yield 58.3%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.92 (dd, J=1.6, 2.3 Hz, 1H),7.23-7.26 (m, 1H), 7.35-7.40 (m, 2H), 7.65 (s, 1H), 7.64-7.70 (m, 2H),12.21 (brs, 1H).

elemental analysis (C₁₁H₈N₂)

Calculated: C:78.55, H:4.79, N:16.66.

Found: C:78.50, H:4.78, N:16.69.

melting point 150.0-151.0° C.

Example 40 5-(4-fluorophenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(4-fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g).Quantification by HPLC gave the title compound (1.43 g, yield 77.8%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.88 (dd, J=1.7, 2.2 Hz, 1H),7.18-7.24 (m, 2H), 7.66-7.71 (m, 3H), 12.20 (brs, 1H).

elemental analysis (C₁₁H₇N₂F)

Calculated: C:70.96, H:3.78, N:15.04, F:10.20.

Found: C:70.99, H:3.74, N:15.16.

melting point 158.4-159.3° C.

Example 41 5-(4-chlorophenyl)-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using [2-(4-chlorophenyl)-2-oxoethyl]propanedinitrile (5.0 g).Quantification by HPLC gave the title compound (2.2 g, yield 48.8%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 6.96 (dd, J=1.6, 2.5 Hz, 1H), 7.43 (d,J=8.7 Hz, 2H), 7.65 (s, 1H), 7.67 (d, J=8.7 Hz, 2H), 12.26 (brs, 1H).

elemental analysis (C₁₁H₇N₂Cl)

Calculated: C:65.20, H:3.47, N:13.82, Cl:17.50.

Found: C:65.45, H:3.49, N:13.81.

melting point 174.2-175.1° C.

Example 42 4-methyl-5-phenyl-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using (1-methyl-2-oxo-2-phenylethyl)propanedinitrile (1.00 g).Quantification by HPLC gave the title compound (624 mg, yield 71.1%).1H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.23 (s, 3H), 7.27-7.30 (m, 1H),7.39-7.50 (m, 4H), 7.59 (d, J=2.3 Hz, 1H), 11.88 (brs, 1H).

elemental analysis (C₁₂H₁₀N₂)

Calculated: C:79.10, H:5.53, N:15.37.

Found: C:79.02, H:5.50, N:15.42.

melting point 130.0-134.5° C. dec.

Example 43 4,5-diphenyl-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using (2,2-diphenylethyl-2-oxo)propanedinitrile (1.00 g).Quantification by HPLC gave the title compound (556 mg, yield 45.2%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 7.10-7.38 (m, 10H), 7.80 (d, J=3.1 Hz,1H), 12.21 (brs, 1H).

elemental analysis (C₁₇H₁₂N₂)

Calculated: C:83.58, H:4.94, N:11.47.

Found: C:83.30, H:5.08, N:11.33.

melting point 163.0-166.0° C.

Example 44 5-tert-butyl-1H-pyrrole-3-carbonitrile

The reaction was performed by an operation similar to that in Example 34and using (3,3-dimethyl-2-oxobutyl)propanedinitrile (1.00 g).Quantification by HPLC gave the title compound (682 mg, yield 75.5%).This was further purified by column chromatography (ethylacetate/n-hexane) to give the title compound (0.54 g, yield 59.4%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 1.20 (s, 9H), 6.07 (dd, J=2.3, 1.8 Hz,1H), 7.42 (dd, J=2.9, 1.8 Hz, 1H), 11.46 (brs, 1H).

elemental analysis (C₉H₁₂N₂)

Calculated: C:72.94, H:8.16, N:18.90.

Found: C:72.68, H:8.24, N:19.03.

melting point 101.5-103.0° C.

Example 45 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile

N,N-Dimethylacetamide (4 ml),[2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile (500 mg, 2.47 mmol) andtriethylamine (5.51 g, 54.41 mmol) were added in a flask, andice-cooled. Formic acid (2.28 g, 49.46 mmol) was added dropwise whilepaying attention to heat generation. The mixture was warmed to roomtemperature, and purged with an inert gas. 5% Pd—C (N.E. CHEMCAT, 500mg) was added, and the mixture was reacted at room temperature for 2.5hr. Acetic acid (2 ml) was added to the reaction mixture, and themixture was reacted at an outer temperature of 50° C. for 1 hr 10 min.The catalyst was filtered off, and washed with THF (about 5 ml).Quantification of the filtrate by HPLC gave the title compound (189 mg,yield 41.0%).

Example 46 Methyl 5-(2-fluorophenyl)-1H-pyrrole-3-carboxylate

Methyl 2-cyano-4-(2-fluorophenyl)-4-oxobutanoate (500 mg, 2.13 mmol) wasdissolved in THF (5 ml), and 5% Pd/C (50% wet, 200 mg) was added. Undera hydrogen atmosphere, the mixture was stirred at room temperature for 4hr. The catalyst was filtered off, and washed with THF. The filtrate wasconcentrated under reduced pressure, THF (10 ml) and acetic acid (10 ml)were added, and the mixture was stirred at room temperature for 1 hr.Quantification of the reaction mixture by HPLC confirmed production ofthe title compound (249 mg, yield 53.5%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 3.85 (3H, s), 7.01-7.27 (4H, m),7.49-7.65 (2H, m), 9.30 (1H, brs).

elemental analysis (C12H₁₀NO₂F)

Calculated: C:65.75, H:4.60, N:6.39, 0:14.59, F:8.66.

Found: C:65.46, H:4.62, N:6.36.

melting point 152.3-152.7° C.

Example 47

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol),acetic acid (30 ml) and THF (15 ml) were weighed and dissolved (under anargon atmosphere). Then, Raney-nickel (0.5 ml) and water (4.5 ml) wereweighed and added, and the mixture was purged with hydrogen. This wasreacted at room temperature for about 8 hr. Quantification of thefiltrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (654mg, yield 35.6%).

Example 48

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol),acetic acid (22 ml) and THF (22 ml) were weighed and dissolved (under anargon atmosphere). Then, Raney-nickel (0.5 ml) and water (4.5 ml) wereweighed and added, and the mixture was purged with hydrogen. This wasreacted at room temperature for about 9 hr. Quantification of thefiltrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (831mg, yield 45.2%).

Example 49

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol),acetic acid (6 ml) and THF (22 ml) were weighed and dissolved (under anargon atmosphere). Then, Raney-nickel (0.5 ml) and water (4.5 ml) wereweighed and added, and the mixture was purged with hydrogen. This wasreacted at room temperature for about 9 hr. Quantification of thefiltrate by HPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (682mg, yield 37.1%).

Example 50

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol),N,N-dimethylformamide (10 ml) and ammonium formate (3.2 g) were weighedand dissolved (under an argon atmosphere). Then, 5% Pd—C (600 mg) wasadded, and the mixture was reacted at room temperature for about 1 hr,and at an outer temperature of 50° C. for about 2 hr. The catalyst wasfiltered off, and the filtrate was quantified by HPLC to give5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (0.089 g, yield 9.70%)

Example 51

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol) andformic acid (6 ml) were weighed and dissolved (under an argonatmosphere). Then, Raney-nickel (0.5 ml) and water (4.5 ml) were weighedand added, and the mixture was purged with hydrogen. 5% Pd—C (600 mg)was added, and the mixture was reacted at an outer temperature of 50° C.for about 5 hr (triethylamine (0.2 ml), formic acid (3 ml) and 5% Pd—C(600 mg) were added during reaction). The catalyst was filtered off, andthe filtrate was quantified by HPLC to give5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (230 mg, yield 24.9%).

Example 52

[2-(2-Fluorophenyl)-2-oxoethyl]propanedinitrile (2.00 g, 9.89 mmol),acetic acid (22 ml) and THE (22 ml) were weighed and dissolved (under anargon atmosphere). Then, Raney-nickel (1 ml) and water (2 ml) wereweighed and added, and the mixture was purged with hydrogen. This wasreacted at 45-50° C. for about 5 hr. Quantification of the filtrate byHPLC gave 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile (718 mg, yield38.6%) and 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (277 mg, yield14.8%).

Example 532,2′-disulfanediylbis[5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile]

To a slurry of [2-(2-methylphenyl)-2-oxoethyl]propanedinitrile obtainedin Reference Example 4 and methanol were added thioacetic acid (66.6 ml,932 mmol), triethylamine (13.0 ml, 93.2 mmol) and dimethyl sulfoxide(8.59 ml, 121 mmol), and the mixture was heated under reflux at theinternal temperature of about 60° C. for 13 hr. The reaction mixture wasgradually cooled to 30° C. or below, further cooled to an internaltemperature of 5±5° C. and stirred for 1 hr. The precipitated crystalswere collected by filtration, and washed with cold ethanol (62.5 ml).The wet crystals were dried under reduced pressure at 50° C. to give thetitle compound (56.4 g, yield 57%) as yellow crystals.

melting point 248.0-249.0° C.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 12.7 (s, 2H), 7.41 (d, J=6.0 Hz, 2H),7.31-7.26 (m, 6H), 6.78 (d, J=2.4 Hz, 2H), 2.40 (s, 6H).

elemental analysis (C₂₄H₁₈N₄S₂)

Calculated: C, 67.58; H, 4.25; N, 13.13; S, 15.03.

Found: C, 67.40; H, 4.20; N, 13.04; S, 14.92.

LC-MS: 426 (M+).

Example 54 5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile

Raney-nickel (139 g), N,N-dimethylformamide (300 ml) and morpholine(15.5 ml, 178 mmol) were added in a four neck flask, and the mixture wasstirred under a nitrogen stream at room temperature. While maintainingthe internal temperature at 40° C. or below, a solution of2,2′-disulfanediylbis[5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile] (50g, 117 mmol) in N,N-dimethylformamide (150 ml) was slowly addeddropwise. The dropping funnel was washed with N,N-dimethylformamide (50ml). The mixture was heated under reflux at the internal temperature of100-110° C. for 1.5 hr. After cooling to room temperature, Raney-nickelwas filtered off, and the residue was washed with ethyl acetate (150ml). Ethyl acetate (350 ml) and 10% brine (750 ml) were added to thefiltrate for extraction and partitioning. The aqueous layer wasextracted with ethyl acetate (250 ml, 125 ml, 125 ml). The organiclayers were combined, washed with water (1 L) and concentrated to abouthalf amount under reduced pressure. Ethanol (250 ml) was added to theconcentrate, and the mixture was concentrated to about 241 g. Thisoperation was repeated 3 times. Water (250 ml) was added while stirringthe concentrate with heating at 75-85° C., and the mixture was furtherstirred at the same temperature for 1 hr. The mixture was graduallycooled to not more than 30° C., further cooled to the internaltemperature of 5±5° C., and stirred for 1 hr. The precipitated crystalswere collected by filtration, and washed with a cold mixture of ethanol(37.5 ml) and water (37.5 ml). The wet crystals were dried under reducedpressure at 50° C. until a constant weight was reached to give the titlecompound (35.5 g, yield 83%).

melting point 151-152° C.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.37 (s, 3H), 6.61 (d, J=1.36 Hz, 1H),7.23-7.31 (m, 3H), 7.38-7.41 (m, 1H), 7.71 (d, J=1.36 Hz, 1H), 11.98(brs, 1H).

elemental analysis (C₁₂H₁₀N₂)

Calculated: C, 79.09; H, 5.52; N, 15.37.

Found: C, 78.94; H, 5.55; N, 15.26.

Example 55S-[3-cyano-5-(2-methylphenyl)-1H-pyrrol-2-yl]benzenecarbonitrile

[2-(2-Methylphenyl)-2-oxoethyl]propanedinitrile (10 g, 50.4 mmol),thiobenzoic acid (11.2 g, 81.0 mmol), triethylamine (508 mg, 5.04 mmol)and methanol (100 ml) were mixed, and the mixture was stirred at about60° C. for about 3 hr. Water (10 ml) was added at about 35° C., and themixture was stirred at room temperature for 1 hr, and at about 10° C.for about 1 hr. The precipitated crystals were collected by filtration,and washed with a mixture of methanol (24 ml) and water (6 ml). The wetcrystals were dried under reduced pressure to give the title compound(14.4 g, yield 90%). 1H-NMR (300 MHz, DMSO-d₆) δ(ppm): 2.40 (s, 3H),6.90 (s, 1H), 7.28-7.30 (m, 3H), 7.40-7.43 (m, 1H), 7.65 (t, J=7.6 Hz,2H), 7.78-7.80 (m, 1H), 8.02-8.05 (m, 2H), 12.6 (brs, 1H)

Example 56 5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile

Raney-nickel (73 g), N,N-dimethylformamide (150 ml) and morpholine (13.0ml, 149 mmol) were added in a four neck flask, and the mixture wasstirred under a nitrogen stream at room temperature. While maintainingthe internal temperature at 40° C. or below, a solution ofS-[3-cyano-5-(2-methylphenyl)-1H-pyrrol-2-yl]benzenecarbonitrile (31.6g, 99.2 mmol) in N,N-dimethylformamide (130 ml) was slowly addeddropwise. The dropping funnel was washed with N,N-dimethylformamide (30ml). The mixture was heated under reflux at the internal temperature of100-110° C. for 1.5 hr. After cooling to room temperature, Raney-nickelwas filtered off, and the residue was washed with ethyl acetate (210ml). Ethyl acetate (210 ml) and 10% brine (750 ml) were added to thefiltrate for extraction and partitioning. The aqueous layer wasextracted with ethyl acetate (150 ml, 75 ml, 75 ml). The organic layerswere combined, washed with water (210 ml) and concentrated under reducedpressure. Ethanol (212 ml) was added to the concentrate, and the mixturewas concentrated to about 204 g. This operation was repeated 3 times.Water (210 ml) was added while stirring the concentrate with heating at75-85° C., and the mixture was further stirred at the same temperaturefor 1 hr. The mixture was gradually cooled to not more than 30° C.,further cooled to the internal temperature of 5±5° C., and stirred for 1hr. The precipitated crystals were collected by filtration, and washedwith a cold mixture of ethanol (4.5 ml) and water (10.5 ml). The wetcrystals were dried under reduced pressure at 50° C. until a constantweight was reached to give the title compound (14.1 g, yield 78%).

Example 575-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile

5-(2-Methylphenyl)-1H-pyrrole-3-carbonitrile (35.0 g, 192 mmol),acetonitrile (131 ml), 4-N,N-dimethylaminopyridine (4.69 g, 38.4 mmol)and diisopropylethylamine (269 mmol, 46.1 ml) were added in a four neckflask, and the mixture was stirred at room temperature. Whilemaintaining an internal temperature at 40° C. or below, a solution of3-pyridinesulfonyl chloride (40.9 g, 230 mmol) in acetonitrile (37 ml)was slowly added dropwise, the dropping funnel was washed withacetonitrile (7 ml). The mixture was reacted at room temperature for 1hr, and tap water (87.5 ml) was added to the reaction mixture. 0.5 N HClwas added dropwise to adjust to pH 4.5, and the mixture was stirred atroom temperature for 1 hr. The precipitated crystals were collected byfiltration, and washed with a mixture of acetonitrile (21.2 ml) andwater (21.2 ml). The wet crystals were dried under reduced pressure at50° C. to give the title compound (54.8 g, yield 90%). 1H-NMR (300 MHz,CDCl₃) δ (ppm): 8.81 (d, J=1.8 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.01 (s,1H), 7.60-7.56 (br, 1H), 7.38-7.18 (m, 4H), 6.88 (d, J=7.5 Hz, 1H), 6.56(s, 1H), 1.82 (s, 3H).

Example 585-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehydehydrochloride

5-(2-Methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile(123.6 mmol, 40.0 g), tetrahydrofuran (160 ml), acetic acid (240 ml),water (240 ml) and Raney-nickel (32.0 g) were added in a four neckflask, and the mixture was reacted under slightly pressurized hydrogenat 17-25° C. for 9 hr. After completion of the reaction, the catalystwas filtered off, and washed with a mixture of tetrahydrofuran (15 ml),acetic acid (22.5 ml) and water (22.5 ml). The filtrate was extractedwith ethyl acetate (400 ml) and tap water (400 ml). The organic layerwas washed twice with tap water (200 ml), and partitioned. The organiclayer was concentrated under reduced pressure to about 60 g, ethylacetate (200 ml) was added to the concentrate, and the mixture wasconcentrated again under reduced pressure to about 60 g. This operationwas performed twice in total. Ethyl acetate (300 ml) was added to adjustthe liquid amount to about 330 g. To the ethyl acetate solution wasslowly added dropwise 4 N hydrochloric acid/ethyl acetate solution (62ml, 247 mmol) at 25-35° C. After the completion of the dropwiseaddition, the mixture was stirred at the internal temperature of 50-55°C. for 1 hr. The suspension was cooled to 20-30° C., and stirred at thesame temperature for 1 hr, and further at 0-10° C. for 1 hr. Theprecipitated crystals were collected by filtration, and washed withethyl acetate (80 ml) The wet crystals were dried under reduced pressureat 50° C. until a constant weight was reached to give the title compound(38 g, yield 85%).

¹H-NMR (500 MHz, DMSO-d₆) δ(ppm): 1.74 (s, 3H), 6.58 (d, J=1.58 Hz, 1H),6.83-6.91 (m, 1H), 7.11-7.25 (m, 2H), 7.38 (td, J=7.57, 1.26 Hz, 1H),7.62 (dd, J=8.20, 4.73 Hz, 1H), 7.85-7.94 (m, 1H), 8.47 (d, J=1.89 Hz,1H), 8.56 (d, J=1.58 Hz, 1H), 8.91 (dd, J=4.73, 1.58 Hz, 1H), 9.90 (s,1H), 1H not detected.

Example 59N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

Under a nitrogen stream, 40% methylamine methanol solution (21.2 ml, 207mmol) and methanol (60 ml) were added in a four neck flask, and asolution of5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehydehydrochloride (30 g, 82.7 mmol) in N,N-dimethylformamide (90 ml) wasadded dropwise at 30° C. or below. The mixture was stirred at about 25°C. for 1 hr, Na₂CO₃ (8.76 g, 82.7 mmol) was added, and the mixture wasfurther stirred for 1 hr. The mixture was ice-cooled to 0-5° C., asolution of sodium borohydride (1.56 g, 41.3 mmol) inN,N-dimethylformamide (30 ml) was slowly added dropwise at 10° C. orbelow. The mixture was stirred at 0-5° C. for 1 hr, 2 N hydrochloricacid (200 ml) was added dropwise at 15° C. or below to adjust to pH 2,and the mixture was stirred at room temperature for 1 hr. Ethyl acetate(300 ml) and 12.5% aqueous ammonia (180 ml) were added, and the mixturewas stirred at room temperature for 30 min and partitioned. The aqueouslayer was extracted with ethyl acetate (180 ml). The organic layers werecombined, washed with about 5% brine (180 ml) and partitioned. Theorganic layer was concentrated to 40 g, ethyl acetate (300 ml) was addedand the mixture was concentrated again. This operation was performedtwice, and the mixture was concentrated to the total amount of 165 g.N,N-Dimethylformamide (150 ml) was added to the concentrated residue,and the mixture was heated to the internal temperature of 50-60° C.Fumaric acid (9.6 g, 82.7 mmol) was added. The mixture was stirred atthe internal temperature of 50-60° C. for 30 min, allowed to cool andstirred at 20-30° C. for 1 hr, and further stirred at 0-10° C. for 1 hr.The precipitated crystals were collected by filtration, and washed witha cold mixture of N,N-dimethylformamide (30 ml) and ethyl acetate (30ml). The wet crystals were dried under reduced pressure at 50° C. untila constant weight was reached to give the title compound as a crudeproduct (24.5 g, yield 65%).

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 8.88-8.86 (m, 1H), 8.44 (s, 1H),7.81-7.78 (m, 1H), 7.67 (s, 1H), 7.61-7.56 (m, 1H), 7.34 (t, J=7.5 Hz,1H), 7.21-7.12 (m, 2H), 6.84 (d, J=6.7 Hz, 1H), 6.47 (s, 2H), 6.32 (s,1H), 3.85 (s, 2H), 2.43 (s, 3H), 1.81 (s, 3H), 1H not detected.

elemental analysis (C22H₂₃N₃O₆S)

Calculated: C, 57.76; H, 5.07; N, 9.18; S, 7.01; 0, 20.98.

Found: C, 57.87; H, 5.03; N, 9.24; S, 7.00.

A crude product (100 g) ofN-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate and 10% hydrous methanol (900 ml) were added in a four neckflask, and the mixture was dissolved by heating. Insoluble material wasfiltered off, and washed with 10% hydrous methanol (100 ml). Thefiltrate was heated again to the refluxing temperature, and stirred for30 min. After cooling to 40-45° C., the mixture was stirred at the sametemperature for 1 hr, at room temperature for 16 hr, and further at 10°C. or below for 1 hr. The precipitated crystals were collected byfiltration, and washed with cold 50% hydrous methanol (100 ml). The wetcrystals were dried under reduced pressure at 50° C. until a constantweight was reached to give the title compound (72 g, yield 72%).

Example 60S-[3-cyano-5-(2-methylphenyl)-1H-pyrrol-2-yl]benzenecarbonitrile

[2-(2-Methylphenyl)-2-oxoethyl]propanedinitrile (30 g, 151.3 mmol),thiobenzoic acid (28.5 ml, 243 mmol), triethylamine (2.1 ml, 15.1 mmol)and methanol (300 ml) were mixed, and stirred at about 60° C. for about4 hr. Water (30 ml) was added at about 36° C., and the mixture wasstirred at about 10° C. for about 2 hr. The precipitated crystals werecollected by filtration, and washed with a mixture of methanol (72 ml)and water (18 ml). The wet crystals were dried under reduced pressure togive the title compound (44.2 g, yield 91.7%).

Example 61 5-(2-methylphenyl)-1H-pyrrole-3-carbonitrile

Raney-nickel (92 g), water (100 ml), N,N-dimethylacetamide (200 ml) andmorpholine (16.4 ml, 187.1 mmol) were mixed. A solution ofS-[3-cyano-5-(2-methylphenyl)-1H-pyrrol-2-yl]benzenecarbonitrile (40.0g, 125.6 mmol) in N,N-dimethylacetamide (200 ml) was added dropwise tothe mixture at room temperature. After stirring at about 100° C. forabout 3 hr, the mixture was cooled to 30° C. under a nitrogen stream.Raney-nickel was filtered off and ethyl acetate (400 ml) was added tothe filtrate. The mixture was washed with 10% aqueous sodium chloridesolution (646 ml) and water (580 ml). The organic layer was concentratedunder reduced pressure to about a one-fifth amount, ethanol (141 ml) wasadded, and the mixture was concentrated to about 134 ml. Water (188 ml)was added dropwise at about 80° C., and the mixture was stirred at about5° C. for about 2 hr. The precipitated crystals were collected byfiltration, and washed with a mixture of ethanol (35 ml) and water (47ml). The wet crystals were dried under reduced pressure to give thetitle compound (20.9 g, yield 87.1%).

Example 625-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile

5-(2-Methylphenyl)-1H-pyrrole-3-carbonitrile (18.0 g, 98.8 mmol),acetonitrile (67 ml), diisopropylethylamine (23.7 ml, 138 mmol) and4-N,N-dimethylaminopyridine (2.41 g, 19.7 mmol) were mixed. A solutionof 3-pyridinesulfonyl chloride (21.3 g, 118 mmol) in acetonitrile (23ml) was added dropwise at about 30° C. The mixture was stirred at roomtemperature for about 3 hr, water (50 ml) was added dropwise, and 0.5 Nhydrochloric acid was added dropwise to adjust to pH 4. The precipitatedcrystals were collected by filtration, washed with a mixture ofacetonitrile (11 ml) and water (11 ml). The wet crystals were driedunder reduced pressure to give the title compound (25.8 g, yield 80.7%).

Example 635-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehydehydrochloride

Under a nitrogen stream, water (60 ml), acetic acid (60 ml),tetrahydrofuran (40 ml),5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile(10.0 g) and Raney-nickel (8 g) were mixed. The mixture was stirred atabout 25° C. and internal hydrogen pressure of 0.001-0.008 MPa for about10 hr. After completion of the reaction, Raney-nickel was filtered off,and washed with a mixture of tetrahydrofuran (3.8 ml), acetic acid (5.6ml) and water (5.6 ml). To the filtrate and washings were added ethylacetate (100 ml) and water (100 ml) for partitioning, and the organiclayer was concentrated under reduced pressure. Ethyl acetate (50 ml) wasadded, and the mixture was concentrated under reduced pressure to about83 g. 4 N hydrochloric acid/ethyl acetate solution (15 ml) was addeddropwise at room temperature, and the mixture was stirred at about 50°C. for about 1 hr and at about 10° C. for about 1 hr. The precipitatedcrystals were collected by filtration, and washed with ethyl acetate (20ml). The wet crystals were dried under reduced pressure to give thetitle compound (9.5 g, yield 85%).

Example 64N-methyl-1-[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methanaminefumarate

5-(2-Methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehydehydrochloride (20.0 g, 55.1 mmol), ethyl acetate (200 ml) and water (60ml) were mixed and partitioned. The organic layer was concentrated underreduced pressure. N,N-Dimethylacetamide (60 ml) was added, and a mixtureof 40% methylamine methanol solution (14.3 ml) and methanol (120 ml) wasadded dropwise at about 10° C. A mixture of sodium borohydride (834 mg)and N,N-dimethylacetamide (20 ml) was added dropwise at about −2° C. 4 NHydrochloric acid was added dropwise at about 3° C. to adjust to aroundpH 2. Ethyl acetate (240 ml), water (190 ml) and 25% aqueous ammonia (80ml) were added for partitioning, and the organic layer was washed with5% brine (110 ml) and water (104 ml). The organic layer was concentratedunder reduced pressure, N,N-dimethylformamide (40 ml) and fumaric acid(6.40 g) were added, and the mixture was stirred at about 60° C. forabout 3 hr. Ethyl acetate (80 ml) was added at room temperature, and themixture was stirred at about 5° C. for about 3 hr. The precipitatedcrystals were collected by filtration, and washed with ethyl acetate(120 ml). The wet crystals were dried under reduced pressure to give thetitle compound as a crude product (16.7 g, yield 65.7%).

To a crude product (15.0 g) of the title compound was added 20% hydrousmethanol (120 ml), and the mixture was dissolved by heating. Activatedcarbon was added, and the mixture was stirred at about 60° C. for about10 min. The activated carbon was filtered off, and purified water (200ml) was added at about 30° C. After stirring for about 2 hr, the mixturewas stirred at about 10° C. for about 1 hr. The precipitated crystalswere collected by filtration, washed with 50% hydrous methanol (60 ml).The wet crystals were dried under reduced pressure, and dried crystalswere pulverized to give the title compound (13.0 g, yield 86.7%).

INDUSTRIAL APPLICABILITY

Sulfonylpyrrole compound (VIII) obtained by the method of the presentinvention is useful as an acid secretion inhibitor (proton pumpinhibitor). In addition, 3-cyanopyrrole compound (III) obtained by themethod of the present invention is useful as an intermediate forproducing sulfonylpyrrole compound (VIII).

This application is based on patent application No. 2009-042975 filed inJapan, the contents of which are encompassed in full herein.

The invention claimed is:
 1. A method of producing a compoundrepresented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R5 is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup or a group represented by —S—R⁶ (R⁶ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group), andn is 0, 1 or 2, or a salt thereof, comprising reacting a compoundrepresented by the formula

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the formulaR⁵S(O)_(n)H wherein R⁵ and n are as defined above, or a salt thereof. 2.A method of producing a compound represented by the formula

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, R² is a hydrogen atom, anoptionally substituted alkyl group, an acyl group, an optionallysubstituted hydroxy group, an optionally substituted amino group, achlorine atom or a fluorine atom, R³ is an optionally substitutedhydrocarbon group or an optionally substituted heterocyclic group, andR⁴ is an alkyl group, or a salt thereof, comprising (I) reacting acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof, with acompound represented by the formulaR⁵S(O)_(n)H wherein R⁵ is an optionally substituted hydrocarbon group,an optionally substituted heterocyclic group, an acyl group or a grouprepresented by —S—R⁶ (R⁶ is an optionally substituted hydrocarbon groupor an optionally substituted heterocyclic group), and n is 0, 1 or 2, ora salt thereof, to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, (II)subjecting the obtained compound to a desulfurization reaction to give acompound represented by the formula

wherein each symbol is as defined above, or a salt thereof, (III)reacting the obtained compound with a compound represented by theformulaR³—SO₂—X  (V) wherein R³ is as defined above, and X is a leaving group,or a salt thereof, to give a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, (IV)reducing the obtained compound and hydrolyzing the reduced product togive a compound represented by the formula

wherein each symbol is as defined above, or a salt thereof, and (V)reacting the obtained compound with a compound represented by theformulaR⁴—NH₂  (VII) wherein R⁴ is as defined above, or a salt thereof.
 3. Themethod according to claim 2, wherein the compound represented by theformula (VIII) is1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamineor a salt thereof.